rs28940885

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

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

Publications

14 publications found

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 Gene-Disease associations (from GenCC):

galactose epimerase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Ambry Genetics

GALE links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 9 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Gene score misZ: -0.32246 (below the threshold of 3.09). Trascript score misZ: 0.87424 (below the threshold of 3.09). GenCC associations: The gene is linked to galactose epimerase deficiency.

BP4

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

BP6

Variant 1-23796183-C-T is Benign according to our data. Variant chr1-23796183-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity|other. ClinVar VariationId is 3681.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5 link	c.956G>A	p.Gly319Glu	missense_variant	Exon 11 of 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

GnomAD2 exomes

AF:

0.000354

AC:

AN:

251278

AF XY:

0.000235

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 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

African (AFR)

AF:

0.00326

AC:

109

AN:

33474

American (AMR)

AF:

0.000358

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111978

Other (OTH)

AF:

0.000315

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152314

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00404

AC:

168

AN:

41576

American (AMR)

AF:

0.000196

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68006

Other (OTH)

AF:

0.000948

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000563

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

Mar 26, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1, BS3, PP3, PP4 -

Jun 07, 2018

Eurofins Ntd Llc (ga)

Significance:other

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

Oct 19, 2022

Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3_Supporting, BA1, PP3 -

Jun 21, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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) -

UDPglucose-4-epimerase deficiency

Pathogenic:2Benign:1

Jan 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 24, 2021

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

Assoc with asymptomatic peripheral epimerase deficiency galactosemia in African Americans -

GALE-related disorder

Uncertain:1

Sep 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

3.6

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

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over