1-23798188-C-T

Position:

chr1-23798188-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The ENST00000617979.5(GALE):c.280G>A(p.Val94Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000551 in 1,613,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000060 ( 0 hom. )

Consequence

GALE
ENST00000617979.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.13

Variant links:

Genes affected

GALE (HGNC:4116): (UDP-galactose-4-epimerase) This gene encodes UDP-galactose-4-epimerase which catalyzes two distinct but analogous reactions: the epimerization of UDP-glucose to UDP-galactose, and the epimerization of UDP-N-acetylglucosamine to UDP-N-acetylgalactosamine. The bifunctional nature of the enzyme has the important metabolic consequence that mutant cells (or individuals) are dependent not only on exogenous galactose, but also on exogenous N-acetylgalactosamine as a necessary precursor for the synthesis of glycoproteins and glycolipids. Mutations in this gene result in epimerase-deficiency galactosemia, also referred to as galactosemia type 3, a disease characterized by liver damage, early-onset cataracts, deafness and cognitive disability, with symptoms ranging from mild ('peripheral' form) to severe ('generalized' form). Multiple alternatively spliced transcripts encoding the same protein have been identified. [provided by RefSeq, Jul 2008]

GALE links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain in ENST00000617979.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.892

PP5

Variant 1-23798188-C-T is Pathogenic according to our data. Variant chr1-23798188-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3682.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GALE	NM_001008216.2 linkuse as main transcript	c.280G>A	p.Val94Met	missense_variant	5/12	ENST00000617979.5	NP_001008217.1
GALE	NM_000403.4 linkuse as main transcript	c.280G>A	p.Val94Met	missense_variant	5/12		NP_000394.2
GALE	NM_001127621.2 linkuse as main transcript	c.280G>A	p.Val94Met	missense_variant	4/11		NP_001121093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5 linkuse as main transcript	c.280G>A	p.Val94Met	missense_variant	5/12	1	NM_001008216.2	ENSP00000483375	P1	Q14376-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251262

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000595

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.0000633

AC XY:

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000719

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74370

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000647

Hom.:

Bravo

AF:

0.0000151

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

UDPglucose-4-epimerase deficiency

Pathogenic:5Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 94 of the GALE protein (p.Val94Met). This variant is present in population databases (rs121908047, gnomAD 0.003%). This missense change has been observed in individual(s) with epimerase deficiency galactosemia (PMID: 9973283, 10086948, 28247339). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 3682). 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 not expected to disrupt GALE protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change affects GALE function (PMID: 9973283, 11117433, 16302980). For these reasons, this variant has been classified as Pathogenic. -
not provided, no classification provided	literature only	GeneReviews	-	Identified in homozygous state in persons with severe, generalized form of epimerase deficiency galactosemia -
Likely pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Mar 18, 2022	ACMG classification criteria: PS3 supporting, PS4 moderated, PM2 moderated, PM3 moderated, PP1 moderated, PP3 supporting, PP4 -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Dec 31, 2022	A Homozygous missense variation in exon 5 of the GALE gene that results in the amino acid substitution of Methionine for Valine at codon 94 was detected. The observed variation lies in the BAR domain of APPL family of GALE protein and has previously been reported in patients affected with generalized epimerase deficiency galactosemia and functional evidence showed significant decrease in enzyme activity. The observed variant c.280G>A (p.Val94Met) has not been reported in the 1000 genomes and gnomAD databases and has a minor allele frequency of 0.00793% in our internal database. The in silico prediction of the variant are probably damaging by PolyPhen-2 (HumDiv) and damaging by SIFT, LRT and MutationTaster2. The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Counsyl	Jun 17, 2016	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 19, 2023	Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 9973283); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23732289, 25150110, 16302980, 27604308, 18188677, 6408303, 11279193, 7305435, 10086948, 23644136, 11117433, 9973283, 36056436, 28247339) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 01, 2017	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 12, 2022

The c.280G>A (p.V94M) alteration is located in exon 5 (coding exon 3) of the GALE gene. This alteration results from a G to A substitution at nucleotide position 280, causing the valine (V) at amino acid position 94 to be replaced by a methionine (M). Based on data from gnomAD, the A allele has an overall frequency of <0.01% (3/282652) total alleles studied. The highest observed frequency was <0.01% (1/30614) of South Asian alleles. This alteration has been detected in the homozygous state, or in conjunction with another GALE alteration, in multiple individuals with galactose epimerase deficiency (Reid, 2016; Dias Costa, 2017; Wohlers, 1999; Walter, 1999). This amino acid position is highly conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

Galactosemia III, severe

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 08, 2001

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.41

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;D;T;.;D;D

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

D;.;D;D;.;D

M_CAP

Pathogenic

0.33

MetaRNN

Pathogenic

0.89

D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.6

H;H;.;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.9

.;D;D;D;D;D

REVEL

Pathogenic

0.86

Sift

Uncertain

0.020

.;D;D;D;D;D

Sift4G

Uncertain

0.015

D;D;.;D;.;D

Polyphen

1.0

D;D;.;.;.;.

Vest4

0.93

MVP

0.90

MPC

0.50

ClinPred

0.99

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.72

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