rs28940884

Positions:

chr1-23796722-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000617979.5(GALE):c.770A>G(p.Lys257Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,613,138 control chromosomes in the GnomAD database, including 24 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).

Frequency

Genomes: 𝑓 0.0056 ( 10 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 14 hom. )

Consequence

GALE
ENST00000617979.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:2U:4B:6O:1

Conservation

PhyloP100: 7.35

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00929606).

BP6

Variant 1-23796722-T-C is Benign according to our data. Variant chr1-23796722-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity, other]. Clinvar id is 3679.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Likely_benign=3, Uncertain_significance=2, other=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0056 (852/152276) while in subpopulation AFR AF= 0.0194 (805/41544). AF 95% confidence interval is 0.0183. There are 10 homozygotes in gnomad4. There are 389 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GALE	NM_001008216.2 linkuse as main transcript	c.770A>G	p.Lys257Arg	missense_variant	9/12	ENST00000617979.5	NP_001008217.1
GALE	NM_000403.4 linkuse as main transcript	c.770A>G	p.Lys257Arg	missense_variant	9/12		NP_000394.2
GALE	NM_001127621.2 linkuse as main transcript	c.770A>G	p.Lys257Arg	missense_variant	8/11		NP_001121093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5 linkuse as main transcript	c.770A>G	p.Lys257Arg	missense_variant	9/12	1	NM_001008216.2	ENSP00000483375	P1	Q14376-1

Frequencies

GnomAD3 genomes

AF:

0.00560

AC:

852

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

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:

0.000265

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00141

AC:

351

AN:

248990

Hom.:

AF XY:

0.00108

AC XY:

145

AN XY:

134562

show subpopulations

Gnomad AFR exome

AF:

0.0192

Gnomad AMR exome

AF:

0.000758

Gnomad ASJ exome

AF:

0.000100

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.000823

GnomAD4 exome

AF:

0.000727

AC:

1062

AN:

1460862

Hom.:

Cov.:

AF XY:

0.000644

AC XY:

468

AN XY:

726612

show subpopulations

Gnomad4 AFR exome

AF:

0.0200

Gnomad4 AMR exome

AF:

0.000921

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:

0.000255

Gnomad4 OTH exome

AF:

0.00113

GnomAD4 genome

AF:

0.00560

AC:

852

AN:

152276

Hom.:

Cov.:

AF XY:

0.00522

AC XY:

389

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0194

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00125

Hom.:

Bravo

AF:

0.00594

ESP6500AA

AF:

0.0179

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00175

AC:

213

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity; other

Submissions summary: Pathogenic:2Uncertain:4Benign:6Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

UDPglucose-4-epimerase deficiency

Pathogenic:2Uncertain:1Benign:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Feb 24, 2021	Assoc with asymptomatic peripheral epimerase deficiency galactosemia in African Americans -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 22, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 18, 2024	- -

not provided

Uncertain:2Benign:1Other:1

other, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 14, 2017	- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GALE: BS1, BS2 -
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 19, 2022	PS3_Supporting, BA1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jul 17, 2023	BS1 -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 07, 2022	Variant summary: GALE c.770A>G (p.Lys257Arg) results in a conservative amino acid change in the encoded protein sequence. Two of three in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0014 in 248990 control chromosomes, predominantly at a frequency of 0.019 within the African or African-American subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 17 fold of the estimated maximal expected allele frequency for a pathogenic variant in GALE causing UDPglucose-4-Epimerase Deficiency phenotype (0.0011), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and a majority consensus as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 21, 2024	The p.Lys257Arg variant in GALE is classified as likely benign because it has been identified in 1.9% (1474/75008) of African chromosomes, including 24 total homozygotes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1. -

GALE-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2024

The GALE c.770A>G variant is predicted to result in the amino acid substitution p.Lys257Arg. This variant has been reported in several peripheral epimerase deficiency galactosemia patients (Maceratesi et al. 1998. PubMed ID: 9538513; Openo et al. 2006. PubMed ID: 16385452). However, none of these patients had a second clearly pathogenic GALE variant, and the reported results of in vitro and in vivo studies of the c.770A>G variant are conflicting (Timson 2005. PubMed ID: 16302980; Wasilenko et al. 2005. PubMed ID: 15639193). The c.770A>G variant has been documented with a minor allele frequency of ~2% in an African population, which is high for a pathogenic variant. Although we suspect that this variant is probably benign, its clinical significance is currently uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Uncertain

0.13

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

D;D;T;T;.

Eigen

Benign

0.040

Eigen_PC

Uncertain

0.25

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;.;D;D;D

MetaRNN

Benign

0.0093

T;T;T;T;T

MetaSVM

Uncertain

0.17

MutationAssessor

Benign

0.71

N;N;.;.;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.72

PROVEAN

Benign

-2.0

.;N;N;N;N

REVEL

Uncertain

0.62

Sift

Benign

0.20

.;T;T;T;T

Sift4G

Benign

0.19

T;T;T;.;T

Polyphen

0.057

B;B;.;.;B

Vest4

0.81

MVP

0.90

MPC

0.17

ClinPred

0.027

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.79

gMVP

0.64

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