rs185073540

Positions:

chr14-87965532-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_000153.4(GALC):c.1006G>A(p.Val336Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000593 in 1,613,388 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00030 ( 6 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.656

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:

LOC124903355 (HGNC:):

LOC124903355 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012763262).

BP6

Variant 14-87965532-C-T is Benign according to our data. Variant chr14-87965532-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 314752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965532-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4 linkuse as main transcript	c.1006G>A	p.Val336Met	missense_variant	9/17	ENST00000261304.7	NP_000144.2
LOC124903355	XR_007064295.1 linkuse as main transcript			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 linkuse as main transcript	c.1006G>A	p.Val336Met	missense_variant	9/17	1	NM_000153.4	ENSP00000261304	P1	P54803-1

Frequencies

GnomAD3 genomes

AF:

0.00343

AC:

522

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00383

GnomAD3 exomes

AF:

0.000819

AC:

204

AN:

249038

Hom.:

AF XY:

0.000711

AC XY:

AN XY:

135106

show subpopulations

Gnomad AFR exome

AF:

0.0120

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000266

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000298

AC:

435

AN:

1461210

Hom.:

Cov.:

AF XY:

0.000278

AC XY:

202

AN XY:

726924

show subpopulations

Gnomad4 AFR exome

AF:

0.0106

Gnomad4 AMR exome

AF:

0.000560

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.00343

AC:

522

AN:

152178

Hom.:

Cov.:

AF XY:

0.00309

AC XY:

230

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.0119

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00379

Alfa

AF:

0.0224

Hom.:

2341

Bravo

AF:

0.00396

ESP6500AA

AF:

0.0146

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00108

AC:

131

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Sep 29, 2017	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 03, 2020	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	GALC: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2021	This variant is associated with the following publications: (PMID: 27638593) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jan 12, 2024

Variant summary: GALC c.1006G>A (p.Val336Met) results in a conservative amino acid change located in the Glycosyl hydrolase family 59, catalytic domain of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00082 in 249038 control chromosomes, predominantly at a frequency of 0.012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 5.4 fold of the estimated maximal expected allele frequency for a pathogenic variant in GALC causing Krabbe Disease phenotype (0.0022), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. c.1006G>A has been reported in the literature as a polymorphism detected during newborn screening in infants with low GALC activity referred for diagnostic testing (e.g. Orsini_2016). These report(s) do not provide unequivocal conclusions about association of the variant with Krabbe Disease. At least one publication reports experimental evidence evaluating an impact on protein function. The variant shows GALC enzyme activity equivalent to WT in vitro, suggesting the variant has no damaging effect (e.g. Saavedra-Matiz_2016). The following publications have been ascertained in the context of this evaluation (PMID: 26795590, 27638593). ClinVar contains an entry for this variant (Variation ID: 314752). Based on the evidence outlined above, the variant was classified as likely benign. -

GALC-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 25, 2022

This variant is classified as likely 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

0.078

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.22

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.69

D;.;.;.

Eigen

Benign

-0.032

Eigen_PC

Benign

-0.17

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.94

D;D;D;D

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Uncertain

0.26

MutationAssessor

Uncertain

2.8

M;.;.;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.93

N;N;N;N

REVEL

Uncertain

0.40

Sift

Benign

0.20

T;T;T;T

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.95

P;D;P;.

Vest4

0.098

MVP

0.94

MPC

0.24

ClinPred

0.012

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.065

gMVP

0.62

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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