rs1805078

chr14-87984426-G-Achr14-87984426-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000153.4(GALC):c.550C>T(p.Arg184Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0511 in 1,612,988 control chromosomes in the GnomAD database, including 2,422 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. R184R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.039 (175 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2247 hom.)
• Consequence: GALC NM_000153.4 missense
• Clinical Significance: Benign; other criteria provided, multiple submitters, no conflicts B:7 O:2
• Conservation: PhyloP100: 2.62

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072863996).
• BP6: Variant 14-87984426-G-A is Benign according to our data. Variant chr14-87984426-G-A is described in ClinVar as [Benign, other]. Clinvar id is 92506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87984426-G-A is described in Lovd as [Benign]. Variant chr14-87984426-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALC	NM_000153.4	c.550C>T	p.Arg184Cys	missense_variant	5/17	ENST00000261304.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALC	ENST00000261304.7	c.550C>T	p.Arg184Cys	missense_variant	5/17	1	NM_000153.4	P1

Frequencies

GnomAD3 genomes AF: 0.0388 AC: 5900 AN: 151994 Hom.: 175 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.0495

Gnomad AMR AF: 0.0317

Gnomad ASJ AF: 0.0135

Gnomad EAS AF: 0.00578

Gnomad SAS AF: 0.0346

Gnomad FIN AF: 0.0706

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0565

Gnomad OTH AF: 0.0355

GnomAD3 exomes AF: 0.0417 AC: 10401 AN: 249442 Hom.: 291 AF XY: 0.0428 AC XY: 5796 AN XY: 135326

Gnomad AFR exome AF: 0.00982

Gnomad AMR exome AF: 0.0203

Gnomad ASJ exome AF: 0.0139

Gnomad EAS exome AF: 0.00200

Gnomad SAS exome AF: 0.0382

Gnomad FIN exome AF: 0.0693

Gnomad NFE exome AF: 0.0570

Gnomad OTH exome AF: 0.0423

GnomAD4 exome AF: 0.0523 AC: 76449 AN: 1460876 Hom.: 2247 Cov.: 31 AF XY: 0.0520 AC XY: 37819 AN XY: 726784

Gnomad4 AFR exome AF: 0.00786

Gnomad4 AMR exome AF: 0.0213

Gnomad4 ASJ exome AF: 0.0136

Gnomad4 EAS exome AF: 0.0112

Gnomad4 SAS exome AF: 0.0366

Gnomad4 FIN exome AF: 0.0689

Gnomad4 NFE exome AF: 0.0582

Gnomad4 OTH exome AF: 0.0468

GnomAD4 genome AF: 0.0388 AC: 5896 AN: 152112 Hom.: 175 Cov.: 32 AF XY: 0.0379 AC XY: 2819 AN XY: 74348

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.0315

Gnomad4 ASJ AF: 0.0135

Gnomad4 EAS AF: 0.00579

Gnomad4 SAS AF: 0.0347

Gnomad4 FIN AF: 0.0706

Gnomad4 NFE AF: 0.0565

Gnomad4 OTH AF: 0.0346

Alfa AF: 0.0480 Hom.: 363

Bravo AF: 0.0336

TwinsUK AF: 0.0591 AC: 219

ALSPAC AF: 0.0618 AC: 238

ESP6500AA AF: 0.0114 AC: 44

ESP6500EA AF: 0.0561 AC: 463

ExAC AF: 0.0431 AC: 5212

Asia WGS AF: 0.0210 AC: 74 AN: 3478

EpiCase AF: 0.0526

EpiControl AF: 0.0498

ClinVar

Significance: Benign; other

Submissions summary: Benign:7 Other:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Galactosylceramide beta-galactosidase deficiency Benign:2 Other:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
other, criteria provided, single submitter	clinical testing	Invitae	Jan 06, 2019	- pseudodeficiency allele

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2018

This variant is associated with the following publications: (PMID: 32661301, 26865610, 26795590, 7581365, 21228398, 20981092, 22995991) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D;.;.;.
Eigen	Benign	0.11
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	0.98	D;D;D;D
MetaRNN	Benign	0.0073	T;T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.5	L;.;.;.
MutationTaster	Benign	0.78	D;D;D;D
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-3.8	D;D;D;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.027	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D
Polyphen		0.99	D;P;D;.
Vest4		0.14
MPC		0.43
ClinPred		0.029	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs1805078; hg19: chr14-88450770;