rs28940885

chr1-23796183-C-T

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.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
• Clinical Significance: Conflicting classifications of pathogenicity; other criteria provided, conflicting classifications P:2 U:2 B:1 O:1
• Conservation: PhyloP100: 3.60

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=0.033861995).
• 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 id is 3681.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, other=1}.
• 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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALE	NM_001008216.2	c.956G>A	p.Gly319Glu	missense_variant	11/12	ENST00000617979.5
GALE	NM_000403.4	c.956G>A	p.Gly319Glu	missense_variant	11/12
GALE	NM_001127621.2	c.956G>A	p.Gly319Glu	missense_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALE	ENST00000617979.5	c.956G>A	p.Gly319Glu	missense_variant	11/12	1	NM_001008216.2	P1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 173 AN: 152196 Hom.: 2 Cov.: 32

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: 89 AN: 251278 Hom.: 1 AF XY: 0.000235 AC XY: 32 AN XY: 135884

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.: 0 Cov.: 31 AF XY: 0.0000894 AC XY: 65 AN XY: 727226

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.: 2 Cov.: 32 AF XY: 0.00114 AC XY: 85 AN XY: 74482

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.: 1

Bravo AF: 0.00127

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000428 AC: 52

ClinVar

Significance: Conflicting classifications of pathogenicity; other

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

UDPglucose-4-epimerase deficiency Pathogenic:2 Benign:1

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 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 04, 2024	- -

not provided Uncertain:1 Other:1

Uncertain significance, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 19, 2022	PS3_Supporting, BA1, PP3 -
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).

GALE-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 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. PMID 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	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Uncertain	23
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	D
LIST_S2	Uncertain	0.89	D;.;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.034	T;T;T;T
MetaSVM	Pathogenic	1.0	D
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.65	T
Sift4G	Uncertain	0.013	D;D;D;.
Polyphen		0.95	P;P;.;.
Vest4		0.68
MVP		0.94
MPC		0.37
ClinPred		0.65	D
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

Other links and lift over

dbSNP: rs28940885; hg19: chr1-24122673;