rs367768055

Positions:

chr1-23798712-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The ENST00000617979.5(GALE):c.140A>C(p.Glu47Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,613,828 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

GALE
ENST00000617979.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 7.25

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 Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GALE	NM_001008216.2 linkuse as main transcript	c.140A>C	p.Glu47Ala	missense_variant	4/12	ENST00000617979.5	NP_001008217.1
GALE	NM_000403.4 linkuse as main transcript	c.140A>C	p.Glu47Ala	missense_variant	4/12		NP_000394.2
GALE	NM_001127621.2 linkuse as main transcript	c.140A>C	p.Glu47Ala	missense_variant	3/11		NP_001121093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5 linkuse as main transcript	c.140A>C	p.Glu47Ala	missense_variant	4/12	1	NM_001008216.2	ENSP00000483375	P1	Q14376-1

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

250982

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135684

show subpopulations

Gnomad AFR exome

AF:

0.000370

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:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000178

AC:

AN:

1461644

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000117

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000112

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000362

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000580

Hom.:

Bravo

AF:

0.000113

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

GALE-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2023

The GALE c.140A>C variant is predicted to result in the amino acid substitution p.Glu47Ala. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.040% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/1-24125202-T-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

UDPglucose-4-epimerase deficiency

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 21, 2021

This sequence change replaces glutamic acid with alanine at codon 47 of the GALE protein (p.Glu47Ala). The glutamic acid residue is moderately conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs367768055, ExAC 0.05%). This variant has not been reported in the literature in individuals affected with GALE-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Pathogenic

0.23

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.87

D;D;D;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;.;.;D

M_CAP

Uncertain

0.18

MetaRNN

Pathogenic

0.77

D;D;D;D

MetaSVM

Uncertain

0.47

MutationAssessor

Benign

1.3

L;L;.;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.47

PROVEAN

Uncertain

-4.1

.;D;D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.054

.;T;T;T

Sift4G

Benign

0.13

T;T;.;T

Polyphen

0.57

P;P;D;D

Vest4

0.73

MVP

0.90

MPC

0.57

ClinPred

0.50

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.82

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