14-87934869-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000153.4(GALC):c.1921A>G(p.Thr641Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.991 in 1,609,350 control chromosomes in the GnomAD database, including 790,270 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.96 ( 69977 hom., cov: 31)

Exomes 𝑓: 0.99 ( 720293 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.659

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=9.753622E-7).

BP6

Variant 14-87934869-T-C is Benign according to our data. Variant chr14-87934869-T-C is described in ClinVar as [Benign]. Clinvar id is 92500.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87934869-T-C is described in Lovd as [Benign].

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 rank	MANE	Protein	UniProt
GALC	NM_000153.4 link	c.1921A>G	p.Thr641Ala	missense_variant	Exon 17 of 17	ENST00000261304.7	NP_000144.2	P54803-1A0A0A0MQV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 link	c.1921A>G	p.Thr641Ala	missense_variant	Exon 17 of 17	1	NM_000153.4	ENSP00000261304.2		P54803-1

Frequencies

GnomAD3 genomes

AF:

0.957

AC:

145494

AN:

151984

Hom.:

69937

Cov.:

show subpopulations

Gnomad AFR

AF:

0.861

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.984

Gnomad ASJ

AF:

0.998

Gnomad EAS

AF:

0.937

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:

243168

AN:

246956

Hom.:

119870

AF XY:

0.988

AC XY:

132487

AN XY:

134106

show subpopulations

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:

1.00

Gnomad OTH exome

AF:

0.991

GnomAD4 exome

AF:

0.994

AC:

1448476

AN:

1457248

Hom.:

720293

Cov.:

AF XY:

0.995

AC XY:

721390

AN XY:

725246

show subpopulations

Gnomad4 AFR exome

AF:

0.854

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:

145594

AN:

152102

Hom.:

69977

Cov.:

AF XY:

0.958

AC XY:

71238

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.861

Gnomad4 AMR

AF:

0.984

Gnomad4 ASJ

AF:

0.998

Gnomad4 EAS

AF:

0.937

Gnomad4 SAS

AF:

0.995

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

0.999

Gnomad4 OTH

AF:

0.963

Alfa

AF:

0.991

Hom.:

116757

Bravo

AF:

0.950

TwinsUK

AF:

0.999

AC:

3706

ALSPAC

AF:

0.999

AC:

3852

ESP6500AA

AF:

0.872

AC:

3290

ESP6500EA

AF:

0.999

AC:

8241

ExAC

AF:

0.983

AC:

118661

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

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Benign:5

Mar 06, 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. -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:4

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 27638593, 24078576, 27884173, 20981092, 10477434) -

May 16, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The GALC c.1921A>G (p.Thr641Ala) variant involves the alteration of a non-conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to isoform mismatch). This variant was found in 118335/120404 control chromosomes (58239 homozygotes) at a frequency of 0.9828162, which is approximately 440 times the estimated maximal expected allele frequency of a pathogenic GALC variant (0.0022361), highly suggesting this variant is a benign polymorphism and the ancestral allele. 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, a clinical diagnostic laboratory classified this variant as benign. Taken together, this variant is classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 19, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:3

Oct 27, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.47

CADD

Benign

0.13

DANN

Benign

0.15

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.035

T;T;T

MetaRNN

Benign

9.8e-7

T;T;T

MetaSVM

Benign

-0.95

PrimateAI

Benign

0.28

PROVEAN

Benign

1.4

N;N;N

REVEL

Benign

0.26

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Vest4

0.014

MPC

0.12

ClinPred

0.00033

GERP RS

-3.1

Varity_R

0.028

gMVP

0.60

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

Other links and lift over