rs28940884

chr1-23796722-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001008216.2(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 NM_001008216.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:2 U:1 B:6 O:1
• Conservation: PhyloP100: 7.35

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]

ACMG classification

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, other=1, Likely_benign=3, Uncertain_significance=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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALE	NM_001008216.2	c.770A>G	p.Lys257Arg	missense_variant	9/12	ENST00000617979.5
GALE	NM_000403.4	c.770A>G	p.Lys257Arg	missense_variant	9/12
GALE	NM_001127621.2	c.770A>G	p.Lys257Arg	missense_variant	8/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALE	ENST00000617979.5	c.770A>G	p.Lys257Arg	missense_variant	9/12	1	NM_001008216.2	P1

Frequencies

GnomAD3 genomes AF: 0.00560 AC: 852 AN: 152158 Hom.: 10 Cov.: 32

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.: 6 AF XY: 0.00108 AC XY: 145 AN XY: 134562

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.: 14 Cov.: 35 AF XY: 0.000644 AC XY: 468 AN XY: 726612

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.: 10 Cov.: 32 AF XY: 0.00522 AC XY: 389 AN XY: 74460

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.: 1

Bravo AF: 0.00594

ESP6500AA AF: 0.0179 AC: 79

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00175 AC: 213

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity; other

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

UDPglucose-4-epimerase deficiency Pathogenic:2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 1998	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Feb 24, 2021	Assoc with asymptomatic peripheral epimerase deficiency galactosemia in African Americans -

not provided Uncertain:1 Benign:1 Other: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).
Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 19, 2022	PS3_Supporting, BA1 -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	GALE: BS1, BS2 -

not specified Benign:3

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. -
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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Uncertain	0.13
Cadd	Benign	23
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	D
LIST_S2	Uncertain	0.96	D;.;D;D;D
MetaRNN	Benign	0.0093	T;T;T;T;T
MetaSVM	Uncertain	0.17	D
MutationAssessor	Benign	0.71	N;N;.;.;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.72	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	T
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

Other links and lift over

dbSNP: rs28940884; hg19: chr1-24123212;