14-87941544-A-G

Position:

chr14-87941544-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1PM5BP4_StrongBP6_Very_StrongBA1

The ENST00000261304.7(GALC):c.1685T>C(p.Ile562Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,576,428 control chromosomes in the GnomAD database, including 174,846 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I562K) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.49 ( 19109 hom., cov: 32)

Exomes 𝑓: 0.46 ( 155737 hom. )

Consequence

GALC
ENST00000261304.7 missense

Scores

Clinical Significance

Benign; other criteria provided, multiple submitters, no conflicts B:11O:5

Conservation

PhyloP100: 9.29

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:

GALC (HGNC:):

GALC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in ENST00000261304.7

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-87941544-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2502893.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=4.962683E-4).

BP6

Variant 14-87941544-A-G is Benign according to our data. Variant chr14-87941544-A-G is described in ClinVar as [Benign, other]. Clinvar id is 92497.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-87941544-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.597 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.1685T>C	p.Ile562Thr	missense_variant	15/17	ENST00000261304.7	NP_000144.2	P54803-1A0A0A0MQV0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALC	ENST00000261304.7 linkuse as main transcript	c.1685T>C	p.Ile562Thr	missense_variant	15/17	1	NM_000153.4	ENSP00000261304.2		P54803-1

Frequencies

GnomAD3 genomes

AF:

0.492

AC:

74706

AN:

151734

Hom.:

19079

Cov.:

show subpopulations

Gnomad AFR

AF:

0.603

Gnomad AMI

AF:

0.500

Gnomad AMR

AF:

0.397

Gnomad ASJ

AF:

0.491

Gnomad EAS

AF:

0.186

Gnomad SAS

AF:

0.424

Gnomad FIN

AF:

0.476

Gnomad MID

AF:

0.459

Gnomad NFE

AF:

0.478

Gnomad OTH

AF:

0.486

GnomAD3 exomes

AF:

0.433

AC:

107634

AN:

248542

Hom.:

24679

AF XY:

0.435

AC XY:

58669

AN XY:

134844

show subpopulations

Gnomad AFR exome

AF:

0.610

Gnomad AMR exome

AF:

0.316

Gnomad ASJ exome

AF:

0.485

Gnomad EAS exome

AF:

0.175

Gnomad SAS exome

AF:

0.420

Gnomad FIN exome

AF:

0.479

Gnomad NFE exome

AF:

0.475

Gnomad OTH exome

AF:

0.445

GnomAD4 exome

AF:

0.462

AC:

658766

AN:

1424576

Hom.:

155737

Cov.:

AF XY:

0.462

AC XY:

328556

AN XY:

711174

show subpopulations

Gnomad4 AFR exome

AF:

0.610

Gnomad4 AMR exome

AF:

0.326

Gnomad4 ASJ exome

AF:

0.483

Gnomad4 EAS exome

AF:

0.195

Gnomad4 SAS exome

AF:

0.418

Gnomad4 FIN exome

AF:

0.470

Gnomad4 NFE exome

AF:

0.477

Gnomad4 OTH exome

AF:

0.454

GnomAD4 genome

AF:

0.493

AC:

74789

AN:

151852

Hom.:

19109

Cov.:

AF XY:

0.488

AC XY:

36174

AN XY:

74186

show subpopulations

Gnomad4 AFR

AF:

0.603

Gnomad4 AMR

AF:

0.396

Gnomad4 ASJ

AF:

0.491

Gnomad4 EAS

AF:

0.187

Gnomad4 SAS

AF:

0.425

Gnomad4 FIN

AF:

0.476

Gnomad4 NFE

AF:

0.478

Gnomad4 OTH

AF:

0.491

Alfa

AF:

0.470

Hom.:

41782

Bravo

AF:

0.489

TwinsUK

AF:

0.497

AC:

1843

ALSPAC

AF:

0.485

AC:

1869

ESP6500AA

AF:

0.614

AC:

2248

ESP6500EA

AF:

0.481

AC:

3934

ExAC

AF:

0.440

AC:

53173

Asia WGS

AF:

0.398

AC:

1382

AN:

3478

EpiCase

AF:

0.465

EpiControl

AF:

0.463

ClinVar

Significance: Benign; other

Submissions summary: Benign:11Other:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Benign:5Other:3

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, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The p.Ile562Thr variant in GALC has been identified in 1 Japanese individual with Krabbe disease (PMID: 24252386). This variant is classified as benign for autosomal recessive Krabbe disease because it has been identified in >60% of African chromosomes by ExAC (http://gnomad.broadinstitute.org/). -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
other, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 08, 2019	- pseudodeficiency allele
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Benign and reported on 11-13-2019 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -
not provided, no classification provided	literature only	GeneReviews	-	- -

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 27, 2015	- -

not provided

Benign:2Other:2

not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant identified in multiple GenomeConnect participants. Variant classified as Benign (pseudodeficiency allele) and reported, most recently, on 06-18-2021 by Lab or GTR ID 500031. Variant also classified as Benign and reported on 09-16-2019 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
not provided, no classification provided	phenotyping only	GenomeConnect - Brain Gene Registry	-	Variant reported in multiple GenomeConnect participants by mulitple clinical testing laboratories. Variant classified as other/Benign by all laboratories and reported most recently on 05-11-2022 by Variantxy and on 01-25-2022 by Invitae. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Dr. Philip Payne from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 04, 2018	This variant is associated with the following publications: (PMID: 32661301, 27126738, 26865610, 27535533, 24078576, 26795590, 24252386) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.85

D;.;.;.

Eigen

Uncertain

0.19

Eigen_PC

Benign

0.20

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

D;D;D;D

MetaRNN

Benign

0.00050

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;.;.;.

MutationTaster

Benign

0.99

P;P;P;P

PrimateAI

Benign

0.39

PROVEAN

Uncertain

-3.0

D;D;D;D

REVEL

Uncertain

0.51

Sift

Uncertain

0.017

D;D;T;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

0.46

P;P;P;.

Vest4

0.56

MPC

0.20

ClinPred

0.039

GERP RS

5.7

Varity_R

0.20

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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