rs421466

Positions:

• chr14-87941531-T-A
• chr14-87941531-T-C
• chr14-87941531-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000153.4(GALC):​c.1698A>T​(p.Val566Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.99 in 1,588,716 control chromosomes in the GnomAD database, including 780,039 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (69954 hom., cov: 33)
  • Exomes 𝑓: 0.99 (710085 hom.)
• Consequence: GALC NM_000153.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.00900

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 14-87941531-T-A is Benign according to our data. Variant chr14-87941531-T-A is described in ClinVar as [Benign]. Clinvar id is 92498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87941531-T-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.009 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4	c.1698A>T	p.Val566Val	synonymous_variant	15/17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7	c.1698A>T	p.Val566Val	synonymous_variant	15/17	1	NM_000153.4	ENSP00000261304.2

Frequencies

GnomAD3 genomes AF: 0.957 AC: 145443 AN: 151930 Hom.: 69914 Cov.: 33

Gnomad AFR AF: 0.861

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.984

Gnomad ASJ AF: 0.998

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.994

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.962

GnomAD3 exomes AF: 0.985 AC: 244906 AN: 248700 Hom.: 120738 AF XY: 0.988 AC XY: 133296 AN XY: 134920

Gnomad AFR exome AF: 0.858

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.998

Gnomad EAS exome AF: 0.939

Gnomad SAS exome AF: 0.997

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 0.999

Gnomad OTH exome AF: 0.991

GnomAD4 exome AF: 0.994 AC: 1427972 AN: 1436668 Hom.: 710085 Cov.: 32 AF XY: 0.995 AC XY: 712611 AN XY: 716452

Gnomad4 AFR exome AF: 0.853

Gnomad4 AMR exome AF: 0.991

Gnomad4 ASJ exome AF: 0.998

Gnomad4 EAS exome AF: 0.953

Gnomad4 SAS exome AF: 0.997

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.986

GnomAD4 genome AF: 0.957 AC: 145543 AN: 152048 Hom.: 69954 Cov.: 33 AF XY: 0.958 AC XY: 71209 AN XY: 74316

Gnomad4 AFR AF: 0.861

Gnomad4 AMR AF: 0.984

Gnomad4 ASJ AF: 0.998

Gnomad4 EAS AF: 0.938

Gnomad4 SAS AF: 0.995

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 0.999

Gnomad4 OTH AF: 0.963

Alfa AF: 0.979 Hom.: 18296

Bravo AF: 0.950

Asia WGS AF: 0.960 AC: 3340 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:4

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 19, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 16, 2016	Variant summary: The GALC c.1698A>T (p.Val566Val) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism outcome for this variant. 4/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect ESE site of SQp55. This variant was found in 118550/120624 control chromosomes (58347 homozygotes) at a frequency of 0.9828061, which is approximately 440 times the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361), suggesting this variant is a benign polymorphism. The variant has been found to co-occur in Krabbe Disease patients with compound heterozygous pathogenic variants that would explain the patients phenotype. In addition, one clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

GALC-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 21, 2021

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
BayesDel_noAF	Benign	-0.44
CADD	Benign	5.4
DANN	Benign	0.61

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: rs421466; hg19: chr14-88407875;