rs3213918

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_000153.4(GALC):c.1302C>T(p.Ser434=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 1,598,544 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0075 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0049 ( 91 hom. )

Consequence

GALC
NM_000153.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -1.36

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 14-87949881-G-A is Benign according to our data. Variant chr14-87949881-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 255370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87949881-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-1.36 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00746 (1134/151950) while in subpopulation EAS AF= 0.0432 (222/5134). AF 95% confidence interval is 0.0386. There are 17 homozygotes in gnomad4. There are 568 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4 linkuse as main transcript	c.1302C>T	p.Ser434=	synonymous_variant	12/17	ENST00000261304.7	NP_000144.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 linkuse as main transcript	c.1302C>T	p.Ser434=	synonymous_variant	12/17	1	NM_000153.4	ENSP00000261304	P1	P54803-1

Frequencies

GnomAD3 genomes

AF:

0.00749

AC:

1137

AN:

151832

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00809

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.0435

Gnomad SAS

AF:

0.0307

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.00222

Gnomad OTH

AF:

0.0115

GnomAD3 exomes

AF:

0.00872

AC:

2167

AN:

248572

Hom.:

AF XY:

0.00907

AC XY:

1224

AN XY:

134938

show subpopulations

Gnomad AFR exome

AF:

0.0124

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.000299

Gnomad EAS exome

AF:

0.0387

Gnomad SAS exome

AF:

0.0246

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00232

Gnomad OTH exome

AF:

0.00682

GnomAD4 exome

AF:

0.00493

AC:

7136

AN:

1446594

Hom.:

Cov.:

AF XY:

0.00547

AC XY:

3945

AN XY:

720584

show subpopulations

Gnomad4 AFR exome

AF:

0.0125

Gnomad4 AMR exome

AF:

0.00590

Gnomad4 ASJ exome

AF:

0.000308

Gnomad4 EAS exome

AF:

0.0359

Gnomad4 SAS exome

AF:

0.0236

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.00220

Gnomad4 OTH exome

AF:

0.00886

GnomAD4 genome

AF:

0.00746

AC:

1134

AN:

151950

Hom.:

Cov.:

AF XY:

0.00765

AC XY:

568

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.0111

Gnomad4 AMR

AF:

0.00808

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.0432

Gnomad4 SAS

AF:

0.0305

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00222

Gnomad4 OTH

AF:

0.0114

Alfa

AF:

0.00241

Hom.:

Bravo

AF:

0.00825

Asia WGS

AF:

0.0310

AC:

107

AN:

3476

EpiCase

AF:

0.00268

EpiControl

AF:

0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Benign:4

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Sep 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 16, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 10, 2017

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

GALC-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 15, 2024

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

-0.73

CADD

Benign

1.1

DANN

Benign

0.56

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

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

Other links and lift over