rs28940885

Positions:

chr1-23796183-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_001008216.2(GALE):c.956G>A(p.Gly319Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000199 in 1,614,134 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G319R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

GALE
NM_001008216.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:2U:4B:1O:1

Conservation

PhyloP100: 3.60

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 Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.033861995).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00114 (173/152314) while in subpopulation AFR AF= 0.00404 (168/41576). AF 95% confidence interval is 0.00354. There are 2 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALE	NM_001008216.2 link	c.956G>A	p.Gly319Glu	missense_variant	11/12	ENST00000617979.5	NP_001008217.1	Q14376-1A0A384NL38
GALE	NM_000403.4 link	c.956G>A	p.Gly319Glu	missense_variant	11/12		NP_000394.2	Q14376-1A0A384NL38
GALE	NM_001127621.2 link	c.956G>A	p.Gly319Glu	missense_variant	10/11		NP_001121093.1	Q14376-1A0A384NL38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5 link	c.956G>A	p.Gly319Glu	missense_variant	11/12	1	NM_001008216.2	ENSP00000483375.1		Q14376-1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

173

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00405

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.00

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000354

AC:

AN:

251278

Hom.:

AF XY:

0.000235

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00419

Gnomad AMR exome

AF:

0.000492

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:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000101

AC:

148

AN:

1461820

Hom.:

Cov.:

AF XY:

0.0000894

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00326

Gnomad4 AMR exome

AF:

0.000358

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:

0.00

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152314

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00404

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.000409

Hom.:

Bravo

AF:

0.00127

ESP6500AA

AF:

0.00363

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000428

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:2Uncertain:4Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 26, 2024	BS1, BS3, PP3, PP4 -
other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 07, 2018	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 21, 2024	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: 16302980, 18188677, 30409984, 15639193, 22995991, 9538513, 23644136, 16385452) -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 19, 2022	PS3_Supporting, BA1, PP3 -

UDPglucose-4-epimerase deficiency

Pathogenic:2Benign:1

Pathogenic, no assertion criteria provided	literature only	GeneReviews	Feb 24, 2021	Assoc with asymptomatic peripheral epimerase deficiency galactosemia in African Americans -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	- -

GALE-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2024

The GALE c.956G>A variant is predicted to result in the amino acid substitution p.Gly319Glu. This variant has been reported in two patients with GALE deficiency in erythrocytes and lymphoblasts; one of them was heterozygous for a second amino acid substitution (p.Ser81Arg) (Openo et al. 2006. PubMed ID 16385452). The authors in this study reported moderate to severe enzyme deficiencies based on in vitro activity assays. In contrast, others have reported that this amino acid change does not significantly affect the kinetics or activity of the GALE enzyme, and may therefore be a neutral polymorphism (Timson. 2005. PubMed ID: 16302980; Wasilenko et al. 2005. PubMed ID: 15639193). This variant has been reported at an allele frequency of ~0.4% in an African population, which is relatively high for a pathogenic variant. While we suspect that this variant may possibly be benign, its clinical significance is uncertain due to the conflicting published evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.086

BayesDel_noAF

Pathogenic

0.35

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.94

D;D;D;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

D;.;D;D

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.034

T;T;T;T

MetaSVM

Pathogenic

1.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.4

.;D;D;D

REVEL

Pathogenic

0.94

Sift

Uncertain

0.014

.;D;D;D

Sift4G

Uncertain

0.013

D;D;D;.

Polyphen

0.95

P;P;.;.

Vest4

0.68

MVP

0.94

MPC

0.37

ClinPred

0.65

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.83

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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