chr14-87986582-T-C

Position:

chr14-87986582-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The ENST00000261304.7(GALC):c.349A>G(p.Met117Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,613,194 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M117L) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.00039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000057 ( 0 hom. )

Consequence

GALC
ENST00000261304.7 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:2

Conservation

PhyloP100: 7.99

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 Likely_pathogenic. Variant got 7 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

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr14-87986582-T-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1066196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP5

Variant 14-87986582-T-C is Pathogenic according to our data. Variant chr14-87986582-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92504.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=3, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALC	NM_000153.4 linkuse as main transcript	c.349A>G	p.Met117Val	missense_variant	4/17	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.349A>G	p.Met117Val	missense_variant	4/17	1	NM_000153.4	ENSP00000261304	P1	P54803-1

Frequencies

GnomAD3 genomes

AF:

0.000388

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000843

AC:

AN:

249238

Hom.:

AF XY:

0.0000592

AC XY:

AN XY:

135198

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000177

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000568

AC:

AN:

1460972

Hom.:

Cov.:

AF XY:

0.0000413

AC XY:

AN XY:

726864

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000234

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000388

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

AN XY:

74434

show subpopulations

Gnomad4 AFR

AF:

0.00132

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000646

Hom.:

Bravo

AF:

0.000355

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00151

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Galactosylceramide beta-galactosidase deficiency

Pathogenic:2Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 117 of the GALC protein (p.Met117Val). This variant is present in population databases (rs145580093, gnomAD 0.1%). This missense change has been observed in individual(s) with Krabbe disease (PMID: 23430802, 30089515). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Met101Val. ClinVar contains an entry for this variant (Variation ID: 92504). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GALC protein function with a positive predictive value of 95%. Experimental studies have shown that this missense change affects GALC function (PMID: 27638593). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Jan 09, 2018	- -

not provided

Pathogenic:2Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 26, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Nov 11, 2015	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 06, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;.;.;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Pathogenic

0.32

MetaRNN

Uncertain

0.62

D;D;D;D

MetaSVM

Pathogenic

0.98

MutationAssessor

Pathogenic

3.1

M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.2

D;D;D;D

REVEL

Pathogenic

0.93

Sift

Uncertain

0.020

D;D;D;D

Sift4G

Uncertain

0.011

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.93

MVP

0.94

MPC

0.59

ClinPred

0.41

GERP RS

5.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.46

gMVP

0.92

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