14-87976368-C-T

Variant names:

• chr14-87976368-C-T
• rs34362748
• NM_000153.4:c.742G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000153.4(GALC):​c.742G>A​(p.Asp248Asn) variant causes a missense change. The variant allele was found at a frequency of 0.142 in 1,613,138 control chromosomes in the GnomAD database, including 17,561 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★). Synonymous variant affecting the same amino acid position (i.e. D248D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.11 (1143 hom., cov: 32)
  • Exomes 𝑓: 0.14 (16418 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts U:1 B:8 O:3
• Conservation: PhyloP100: 5.68
• Publications: 47 publications found

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 Gene-Disease associations (from GenCC):

• Krabbe disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Myriad Women’s Health, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000153.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 94 curated pathogenic missense variants (we use a threshold of 10). The gene has 16 curated benign missense variants. Gene score misZ: 0.18582 (below the threshold of 3.09). Trascript score misZ: -0.28853 (below the threshold of 3.09). GenCC associations: The gene is linked to Krabbe disease.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0022206604).
• BP6: Variant 14-87976368-C-T is Benign according to our data. Variant chr14-87976368-C-T is described in ClinVar as Benign|other. ClinVar VariationId is 92509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.154 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALC	NM_000153.4	c.742G>A	p.Asp248Asn	missense_variant	Exon 7 of 17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.742G>A	p.Asp248Asn	missense_variant	Exon 7 of 17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17197 AN: 152054 Hom.: 1140 Cov.: 32

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.141

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0956

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.156

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.126 AC: 31486 AN: 249288 AF XY: 0.126

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.00195

Gnomad FIN exome AF: 0.159

Gnomad NFE exome AF: 0.155

Gnomad OTH exome AF: 0.132

GnomAD4 exome AF: 0.145 AC: 211284 AN: 1460966 Hom.: 16418 Cov.: 32 AF XY: 0.143 AC XY: 104237 AN XY: 726850

African (AFR) AF: 0.0347 AC: 1163 AN: 33476

American (AMR) AF: 0.146 AC: 6527 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 3106 AN: 26132

East Asian (EAS) AF: 0.00159 AC: 63 AN: 39666

South Asian (SAS) AF: 0.102 AC: 8798 AN: 86248

European-Finnish (FIN) AF: 0.163 AC: 8675 AN: 53304

Middle Eastern (MID) AF: 0.162 AC: 933 AN: 5766

European-Non Finnish (NFE) AF: 0.157 AC: 173970 AN: 1111290

Other (OTH) AF: 0.133 AC: 8049 AN: 60368

GnomAD4 genome AF: 0.113 AC: 17206 AN: 152172 Hom.: 1143 Cov.: 32 AF XY: 0.114 AC XY: 8446 AN XY: 74390

African (AFR) AF: 0.0400 AC: 1662 AN: 41544

American (AMR) AF: 0.130 AC: 1992 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 413 AN: 3470

East Asian (EAS) AF: 0.00232 AC: 12 AN: 5174

South Asian (SAS) AF: 0.0954 AC: 460 AN: 4820

European-Finnish (FIN) AF: 0.156 AC: 1652 AN: 10582

Middle Eastern (MID) AF: 0.129 AC: 38 AN: 294

European-Non Finnish (NFE) AF: 0.156 AC: 10621 AN: 67984

Other (OTH) AF: 0.108 AC: 228 AN: 2110

Alfa AF: 0.135 Hom.: 3713

Bravo AF: 0.107

TwinsUK AF: 0.147 AC: 546

ALSPAC AF: 0.153 AC: 590

ESP6500AA AF: 0.0444 AC: 171

ESP6500EA AF: 0.152 AC: 1259

ExAC AF: 0.124 AC: 15018

Asia WGS AF: 0.0550 AC: 191 AN: 3478

EpiCase AF: 0.155

EpiControl AF: 0.155

ClinVar

Significance: Benign; other

Submissions summary: Uncertain:1 Benign:8 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1 Benign:2 Other:1

Oct 26, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

GenomeConnect - Brain Gene Registry

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant reported in multiple GenomeConnect participants by mulitple clinical testing laboratories. Variant classified as other/Benign by all laboratories and reported most recently on 05-11-2022 by Variantxy and on 01-25-2022 by Invitae. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Oct 29, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Galactosylceramide beta-galactosidase deficiency Benign:2 Other:2

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

-

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Jan 06, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- pseudodeficiency allele

not specified Benign:3

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Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 31, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GALC-related disorder Benign:1

Nov 16, 2020

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T;T;T
MetaRNN	Benign	0.0022	T;T;T;T
MetaSVM	Benign	-1.4	T
MutationAssessor	Pathogenic	3.1	M;.;.;.
PhyloP100		5.7
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.4	D;D;D;D
REVEL	Uncertain	0.62
Sift	Benign	0.039	D;D;D;T
Sift4G	Uncertain	0.053	T;T;D;T
Polyphen		0.63	P;P;P;.
Vest4		0.38
MPC		0.39
ClinPred		0.067	T
GERP RS		5.3
Varity_R		0.24
gMVP		0.91
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs34362748; hg19: chr14-88442712; COSMIC: COSV54330950; COSMIC: COSV54330950;