14-87986597-T-C

Position:

chr14-87986597-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP5BP4BS2

The NM_000153.4(GALC):c.334A>G(p.Thr112Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00378 in 1,608,454 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0039 ( 22 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9U:18O:1

Conservation

PhyloP100: 7.99

Variant links:

Genes affected

GALC (HGNC:4115): (galactosylceramidase) This gene encodes a lysosomal protein which hydrolyzes the galactose ester bonds of galactosylceramide, galactosylsphingosine, lactosylceramide, and monogalactosyldiglyceride. Mutations in this gene have been associated with Krabbe disease, also known as globoid cell leukodystrophy. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

GALC links:

GALC (HGNC:):

GALC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP5

Variant 14-87986597-T-C is Pathogenic according to our data. Variant chr14-87986597-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92503.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=13, not_provided=1, Pathogenic=2, Likely_pathogenic=6}. Variant chr14-87986597-T-C is described in Lovd as [Pathogenic]. Variant chr14-87986597-T-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.06605202). . Strength limited to SUPPORTING due to the PP5.

BS2

High Homozygotes in GnomAdExome4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4 linkuse as main transcript	c.334A>G	p.Thr112Ala	missense_variant	4/17	ENST00000261304.7	NP_000144.2	P54803-1A0A0A0MQV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 linkuse as main transcript	c.334A>G	p.Thr112Ala	missense_variant	4/17	1	NM_000153.4	ENSP00000261304.2		P54803-1

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

336

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000652

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000590

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.00207

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00393

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00253

AC:

629

AN:

248976

Hom.:

AF XY:

0.00269

AC XY:

364

AN XY:

135068

show subpopulations

Gnomad AFR exome

AF:

0.000582

Gnomad AMR exome

AF:

0.000987

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.0000556

Gnomad SAS exome

AF:

0.00196

Gnomad FIN exome

AF:

0.00242

Gnomad NFE exome

AF:

0.00407

Gnomad OTH exome

AF:

0.00215

GnomAD4 exome

AF:

0.00395

AC:

5745

AN:

1456238

Hom.:

Cov.:

AF XY:

0.00394

AC XY:

2855

AN XY:

724896

show subpopulations

Gnomad4 AFR exome

AF:

0.000660

Gnomad4 AMR exome

AF:

0.00107

Gnomad4 ASJ exome

AF:

0.0000766

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00192

Gnomad4 FIN exome

AF:

0.00266

Gnomad4 NFE exome

AF:

0.00469

Gnomad4 OTH exome

AF:

0.00289

GnomAD4 genome

AF:

0.00221

AC:

337

AN:

152216

Hom.:

Cov.:

AF XY:

0.00211

AC XY:

157

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.000650

Gnomad4 AMR

AF:

0.000589

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.00207

Gnomad4 NFE

AF:

0.00393

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00337

Hom.:

Bravo

AF:

0.00220

TwinsUK

AF:

0.00324

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.000500

AC:

ESP6500EA

AF:

0.00373

AC:

ExAC

AF:

0.00254

AC:

307

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00474

EpiControl

AF:

0.00433

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9Uncertain:18Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Pathogenic:7Uncertain:8Other:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	May 09, 2024	A heterozygous variant in exon 4 of the GALC gene that results in the amino acid substitution of Alanine for Threonine at codon 112 was detected. The observed variant c.334A>G (p.Thr112Ala) has not been reported in the 1000 genomes database and has MAF of 0.2526% in gnomAD database. The in silico prediction is damaging by MutationTaster and DANN. In summary, the variant meets our criteria to be classified as likely pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 09, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Genetics, Royal Melbourne Hospital	Nov 20, 2020	This sequence change is predicted to replace threonine with alanine at codon 112 of the GALC protein (p.(Thr112Ala), also known as p.Thr96Ala). The threonine residue is evolutionarily conserved (100 vertebrates, UCSC), and is located in the Glycosyl hydrolase family 59 domain in a triosephosphate isomerase barrel (PMID: 21876145). There is a small physicochemical difference between threonine and alanine. The variant is present in a large population cohort at a frequency of 0.25% (rs147313927, 709/280,348 alleles, 4 homozygotes in gnomAD v2.1), with an allele frequency of 0.4% in the European (non-Finnish) population (BS1; gnomAD v2.1). The variant has been identified in the homozygous state and compound heterozygous with a second allele in at least three individuals with Krabbe disease, and reported to segregate with adult-onset predominant cerebellar ataxia with mild spasticity in five affected individuals (PP1_Strong, PM3; PMID: 8687180, 23197103, 26915362, 31053700). The variant has been reported with reduced enzyme activity in patient cells and in in vitro assays. However, there is in vitro and patient enzyme activity evidence that occurrence of the pseudoefficiency variant p.Ile562Thr is required in cis with the variant to produce disease causing GALC deficiency (PMID: 8687180, 26795590, 27638593). Multiple lines of computational evidence predict a deleterious effect for the missense substitution (PP3; 5/6 algorithms). Based on the classification scheme RMH ACMG Guidelines v1.2.1, this variant is classified as a VARIANT OF UNCERTAIN SIGNIFICANCE. Following criteria are met: PP1_Strong, PM3, BS1, PP3. -
Uncertain significance, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 21, 2020	A homozygous missense variant was identified, NM_000153.3(GALC):c.334A>G in exon 4 of the GALC gene. This substitution is predicted to create a minor amino acid change from a threonine to an alanine at position 112 of the protein; NP_000144.2(GALC):p.Thr112Ala. The threonine at this position has very high conservation (100 vertebrates, UCSC), and is located within the Glycosyl hydrolase family 59 functional domain (NCBI, PDB). In silico software predicts this variant to be damaging (PolyPhen2, SIFT, CADD, Mutation Taster). The variant is present in the gnomAD population database at a global population frequency of 0.25% (701 heterozygotes, 4 homozygotes) with a European sub-population frequency of 0.40%. This variant has been previously reported as likely pathogenic in patients with Krabbe disease (Nashabat, M., et al. (2019)), and as a VUS (ClinVar, Orsini, J. J., et al. (2016)). It has also been shown to segregate with disease in one family (Shao, Y. H. et al. (2016)). In addition, functional studies show reduced GALC activity but the effect of this reduction is unknown (Orsini, J. J., et al. (2016), Saavedra-Matiz, C. A. et al. (2016)). Based on information available at the time of curation, this variant has been classified as a VUS. -
Uncertain significance, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 112 of the GALC protein (p.Thr112Ala). This variant is present in population databases (rs147313927, gnomAD 0.4%), and has an allele count higher than expected for a pathogenic variant. This variant has been reported in combination with other GALC variants in individuals affected with late-onset Krabbe disease with evidence of disease co-segregation in one family (PMID: 23197103, 26915362). This variant is also one of the most common variants that is detected in newborns who are referred for low galactocerebrosidase activity on newborn screening, but interestingly, none of the newborns were categorized as high risk for Krabbe disease (PMID: 26795590). One study has suggested that the p.Thr112Ala variant may become a disease-associated allele only when it co-occurs on the same chromosome (in cis) with the p.Ile562Thr polymorphism (PMID: 27638593). However, the evidence is not sufficient to support a pathogenic haplotype at this time. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 92503). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GALC protein function. Experimental studies have shown that this missense change alone causes a mild reduction of GALC enzyme activity in vitro and the effect is exacerbated in the presence of other GALC variants in cis (PMID: 27638593). In summary, while this variant has been reported in individuals with Krabbe disease in the literature, there are multiple homozygous individuals observed in population databases. In addition, clinical and experimental data suggest that co-occurrence in cis with other GALC variant(s) may be required for this variant to be disease-causing (PMID: 27638593). The available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University Hospital Muenster	Mar 28, 2022	ACMG categories: PS3,PM1,PM3,PP3 -
Likely pathogenic, criteria provided, single submitter	research	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Oct 04, 2024	PM1,PP2,PP3,PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Centogene AG - the Rare Disease Company	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 18, 2023	The p.Thr112Ala (NM_000153.3 c.334A>G, also referred to as p.Thr96Ala) variant in GALC has been reported in 4 compound heterozygous individuals with clinical features of late-onset Krabbe disease (Luzi 1996 PMID: 8687180, Debs 2013 PMID: 23197103, and Shao 2016 PMID: 26915362), and segregated in 3 affected siblings (Shao 2016 PMID: 26915362). This variant is also the most common referral for followup testing for Krabbe disease by newborn screening programs in the heterozygous, homozygous, and compound heterozygous states (Orsini 2016 PMID: 26795590). Upon further testing, these newborns were all classified into the moderate-, low-, or no-risk categories. This variant has been identified in 0.4% (508/126254) of European chromosomes and 4 homozygotes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs147313927). This variant has also been reported in ClinVar (Variation ID 92503). In vitro functional studies provide evidence that the p.Thr112Ala variant leads to reduced enzymatic activity, though not at levels as low as variants causing infantile-onset disease (Saavedra-Matiz 2016 PMID: 23509109, Orsini 2016 PMID: 26795590). Computational prediction tools and conservation analysis suggest that the p.Thr112Ala variant may impact the protein, though this information is not predictive enough to determine pathogenicity. In summary, while there is some suspicion for a pathogenic role, the clinical significance of this variant is uncertain and although at least one individual affected during childhood has been reported, has typically been associated with late-onset disease. ACMG/AMP Criteria applied: BS1, PS3_Moderate, PM3, PP1, PP3. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Jun 22, 2023	The missense variant c.334A>G(p.Thr112Ala) in GALC gene has been reported in homozygous / compound heterozygous state in multiple individuals affected with late-onset Krabbe disease with evidence of disease co-segregation in one family (Nashabat et. al., 2019; Shao et. al., 2016). Experimental studies have shown that this missense change alone causes a mild reduction of GALC enzyme activity (Saavedra et. al., 2016). The observed variant has allele frequency of 0.2% with 3 homozygotes in gnomAD eoxmes database. This variant has been reported to the ClinVar database as Likely Benign / Uncertain Significance / Likely Pathogenic / Pathogenic. Multiple lines of computational evidence (Polyphen - probably damaging, SIFT - damaging and MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid change p.Thr112Ala in GALC is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Thr at position 112 is changed to a Ala changing protein sequence and it might alter its composition and physico-chemical properties. However, additonal literature and functional studies will be required to confirm the pathogenicity of the variant conclusively. For these reasons, this variant has been classified as Likely Pathogenic. In the absence of another reportable variant in GALC gene, the molecular diagnosis is not confirmed. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Feb 13, 2020	The GALC c.334A>G (p.Thr112Ala) variant, which was previously referred to as p.Thr96Ala, is a missense variant that has been reported in association with Krabbe disease in several studies. Shao et al. (2016) reported the variant in five members of a French-Canadian family who all presented with adult-onset disease with predominant cerebellar ataxia and mild spasticity. Nashabat et al. (2019) described a 6-year-old female with early-onset Krabbe disease who was homozygous for the p.Thr112Ala variant and showed low galactocerebrosidase enzyme activity in cultured fibroblasts but normal levels in peripheral blood. This variant was also found to be enriched among infants with GALC activity <12% of normal who were identified through newborn screening (Orsini et al. 2016) and has also been reported in a compound heterozygous state in several affected individuals who were also heterozygous for common enzyme activity-lowering variants, including p.Ile562Thr (previously p.Ile546Thr) (Luzi et al. 1996; Debs et al. 2013). Notably, this variant is reported at a frequency of 0.004022 in the European (non-Finnish) population of the Genome Aggregation Database, which also includes four homozygous carriers. Functional studies in COS1 cells showed the p.Thr112Ala-containing enzyme showed approximately 30% of wild type activity; residual activity was even lower when an additional pseudodeficiency variant was co-expressed (Luzi et al. 1996; Saavedra-Matiz et al. 2016). Marshall et al. (2018) asserted that the p.Thr112Ala variant should be considered a disease-causing allele when in cis with a common enzyme activity reducing variant or when in trans with a severe allele. Based on the collective evidence and application of the ACMG criteria, the p.Thr112Ala variant is classified as likely pathogenic for Krabbe disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mendelics	Dec 26, 2023	- -

not provided

Pathogenic:2Uncertain:9

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 05, 2017	- -
Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 22, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen	Oct 23, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 17, 2023	BS1, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 13, 2024	Reported previously in association with later-onset Krabbe disease in two individuals, one of whom had 5 additional coding variants in GALC and the second had 2 additional coding variants, the phase of the other variants in these cases was unknown (PMID: 8687180, 23197103); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27276562, 24082139, 23891399, 27533158, 30609409, 23197103, 27638593, 23509109, 30202406, 31664448, 29481565, 31053700, 24388568, 26915362, 34426522, 32860008, 34065072, 31980526, 8687180, 26795590, 36964991, 36781956, 34531397, 33742171, 31847883, 32483926, 38837642) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	GALC: PS3:Moderate, PP3 -
Uncertain significance, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The GALC p.T112A variant was identified in 106 of 1306 proband chromosomes (frequency: 0.08) from individuals with late-onset Krabbe disease (Orsini_2016_PMID:26795590; Debs_2013_PMID:23197103). This variant was also found to segregate with disease in one family with late-onset Krabbe disease with predominant cerebellar ataxia in five affected individuals, all of whom were compound heterozygous for the GALC p.T112A and p.E198K variants (Shao_2016_PMID:26915362). In many cases, the p.T112A variant is also found in cis with another GALC variant, such as the p.I1546T variant (Luiz_1996_PMID:8687180; Orsini_2016_PMID:26795590). The variant was identified in dbSNP (ID: rs147313927) and ClinVar (classified as uncertain significance by GeneDx, EGL Genetic Diagnostics, Invitae and Mayo Clinic, as likely pathogenic by Laboratory for Molecular Medicine and as likely benign by Mendelics). The variant was identified in control databases in 709 of 280348 chromosomes (4 homozygous) at a frequency of 0.002529 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 516 of 128292 chromosomes (freq: 0.004022), European (Finnish) in 65 of 25000 chromosomes (freq: 0.0026), South Asian in 60 of 30568 chromosomes (freq: 0.001963), Other in 14 of 7138 chromosomes (freq: 0.001961), Latino in 34 of 35290 chromosomes (freq: 0.000963), African in 18 of 24176 chromosomes (freq: 0.000745), Ashkenazi Jewish in 1 of 10352 chromosomes (freq: 0.000097), and East Asian in 1 of 19532 chromosomes (freq: 0.000051). The p.T112 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. A functional GALC expression study conducted on this variant using COS1 cells found reduced GALC activity compared to the wild type, with GALC activity even more significantly reduced when another GALC variant is present with the p.T112A variant (Saavedra-Matiz_2016_PMID:27638593). In summary, this variant is considered a hypomorphic allele which, in combination with other variants in cis or trans, may result in reduced activity. Based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 15, 2023

Variant summary: The variant, GALC c.334A>G (p.Thr112Ala), also reported as p.Thr96Ala in the literature, results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 248976 control chromosomes, predominantly at a frequency of 0.0041 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GALC causing Krabbe Disease phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. The variant, c.334A>G has been reported in the literature in multiple individuals affected with adult onset cases of Krabbe Disease (Globoid Cell Leukodystrophy (GCL), Debs _2013, Luzi _1996 ). In one French Canadian family, the variant was observed in a compound heterozygous genotype with co-segregation across two generations in 5 patients who were diagnosed with adult onset of Krabbe disease (Shao _2016). In newborn screening done for Krabbe disease at New York State, the infants carrying this variant were classified diagnostically in moderate, low, and no-risk categories, but none was classified as being at high risk (Orsini _2016). These data indicate that the variant is likely to be associated with disease with adult onset of Krabbe disease. Recently, this variant has also been reported in the literature in two homozygous individuals diagnosed with Krabbe disease (Alfares_2018, Nashabat_2019). One of these patients had infantile onset of the disease (Nashabat_2019). However, both reports do not unequivocally confirm the biochemical and clinical features of this disease either due to non-reporting of testing information in the patient reported by Alfares_2018 OR normal CSF protein levels, equivocal MRI measurements, conflicting measurements of enzyme activity in blood (normal activity) and fibroblasts (moderate reduction) and no information regarding psychosine levels in the patient reported by Nashabat_2019. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in <30% of normal activity (Saavedra-Martiz_2016). In the same study, the authors also reported the presence of this variant (reported as p.T96A) in a compound heterozygous patient (among confirmed cases of Krabbe's disease) with two other severe mutations, namely p.R53X and p.R204X. This implies that p.T96A is in cis with one of these two severe mutations in this specific patient with Krabbe disease, supporting a non-pathogenic outcome for this variant. Furthermore, the authors conclude that the pathogenicity of this variant in late-onset Krabbe disease is related to its presence with a haplotype in cis with another variant, p.I546T. Fifteen ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=10), likely pathogenic (n=4) or likely benign (n=2). Based on the evidence outlined above, to reflect the variable expressivity and variable penetrance that could be associated with this variant in different genetic backgrounds, it was classified as a VUS-possibly pathogenic -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.44

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

D;.;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.94

D;D;D;D

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.066

T;T;T;T

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.4

M;.;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.7

D;D;D;D

REVEL

Pathogenic

0.90

Sift

Benign

0.39

T;T;T;T

Sift4G

Benign

0.16

T;T;T;T

Polyphen

0.99

D;D;D;.

Vest4

0.92

MVP

0.98

MPC

0.42

ClinPred

0.026

GERP RS

5.4

Varity_R

0.27

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

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