rs74887188

Positions:

chr14-87965625-T-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_000153.4(GALC):c.913A>G(p.Ile305Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0036 in 1,613,152 control chromosomes in the GnomAD database, including 283 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 31 hom., cov: 33)

Exomes 𝑓: 0.0036 ( 252 hom. )

Consequence

GALC
NM_000153.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.92

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 -16 ACMG points.

BP6

Variant 14-87965625-T-C is Benign according to our data. Variant chr14-87965625-T-C is described in ClinVar as [Benign]. Clinvar id is 198993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87965625-T-C is described in Lovd as [Benign]. Variant chr14-87965625-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0933 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4 linkuse as main transcript	c.913A>G	p.Ile305Val	missense_variant	9/17	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.913A>G	p.Ile305Val	missense_variant	9/17	1	NM_000153.4	ENSP00000261304	P1	P54803-1

Frequencies

GnomAD3 genomes

AF:

0.00385

AC:

586

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000459

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0998

Gnomad SAS

AF:

0.00311

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.00806

AC:

2004

AN:

248704

Hom.:

105

AF XY:

0.00749

AC XY:

1011

AN XY:

134912

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.000291

Gnomad ASJ exome

AF:

0.00169

Gnomad EAS exome

AF:

0.0992

Gnomad SAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.000742

Gnomad NFE exome

AF:

0.000746

Gnomad OTH exome

AF:

0.00282

GnomAD4 exome

AF:

0.00357

AC:

5219

AN:

1460960

Hom.:

252

Cov.:

AF XY:

0.00355

AC XY:

2583

AN XY:

726788

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00142

Gnomad4 EAS exome

AF:

0.108

Gnomad4 SAS exome

AF:

0.00269

Gnomad4 FIN exome

AF:

0.000749

Gnomad4 NFE exome

AF:

0.000295

Gnomad4 OTH exome

AF:

0.00469

GnomAD4 genome

AF:

0.00386

AC:

588

AN:

152192

Hom.:

Cov.:

AF XY:

0.00464

AC XY:

345

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.000459

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.100

Gnomad4 SAS

AF:

0.00311

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00470

Hom.:

Bravo

AF:

0.00492

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.000538

AC:

ESP6500EA

AF:

0.000609

AC:

ExAC

AF:

0.00799

AC:

965

Asia WGS

AF:

0.0370

AC:

128

AN:

3478

EpiCase

AF:

0.000382

EpiControl

AF:

0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Benign: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	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Oct 14, 2014

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 26, 2021

This variant is associated with the following publications: (PMID: Wenger[Review], 33191329, 21228398, 24252386, 27638593, 28552323, 9272171, 16607461, 30323943) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.63

D;.;.;.

Eigen

Pathogenic

0.70

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

MetaRNN

Benign

0.0058

T;T;T;T

MetaSVM

Benign

-0.64

MutationAssessor

Pathogenic

3.1

M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Uncertain

0.61

Sift

Uncertain

0.0070

D;D;T;T

Sift4G

Uncertain

0.012

D;D;D;D

Polyphen

0.91

P;D;D;.

Vest4

0.59

MVP

0.96

MPC

0.32

ClinPred

0.035

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.23

gMVP

0.64

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.38

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.38

Position offset: -1

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