rs542486536

chr1-23798161-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001008216.2(GALE):c.307G>T(p.Asp103Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000039 in 1,614,018 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D103G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000038 (0 hom.)
• Consequence: GALE NM_001008216.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 4.67

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALE	NM_001008216.2	c.307G>T	p.Asp103Tyr	missense_variant	5/12	ENST00000617979.5
GALE	NM_000403.4	c.307G>T	p.Asp103Tyr	missense_variant	5/12
GALE	NM_001127621.2	c.307G>T	p.Asp103Tyr	missense_variant	4/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALE	ENST00000617979.5	c.307G>T	p.Asp103Tyr	missense_variant	5/12	1	NM_001008216.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152204 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000735

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251436 Hom.: 0 AF XY: 0.0000809 AC XY: 11 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000791

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000376 AC: 55 AN: 1461814 Hom.: 0 Cov.: 32 AF XY: 0.0000316 AC XY: 23 AN XY: 727208

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152204 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74372

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000576 AC: 7

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

UDPglucose-4-epimerase deficiency Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 20, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 27, 2021	This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 103 of the GALE protein (p.Asp103Tyr). This variant is present in population databases (rs542486536, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with GALE-related conditions. ClinVar contains an entry for this variant (Variation ID: 572886). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2022

The c.307G>T (p.D103Y) alteration is located in exon 5 (coding exon 3) of the GALE gene. This alteration results from a G to T substitution at nucleotide position 307, causing the aspartic acid (D) at amino acid position 103 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Uncertain	0.070
Cadd	Pathogenic	29
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	D;D;T;.;D;D
Eigen	Uncertain	0.27
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.99	D;.;D;D;.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.44	T;T;T;T;T;T
MetaSVM	Uncertain	0.51	D
MutationAssessor	Benign	1.1	L;L;.;.;.;.
MutationTaster	Benign	0.96	D
PrimateAI	Uncertain	0.56	T
Sift4G	Uncertain	0.043	D;D;.;D;.;D
Polyphen		0.60	P;P;.;.;.;.
Vest4		0.58
MutPred		0.49		Loss of ubiquitination at K100 (P = 0.0514);Loss of ubiquitination at K100 (P = 0.0514);.;.;Loss of ubiquitination at K100 (P = 0.0514);Loss of ubiquitination at K100 (P = 0.0514);
MVP		0.91
MPC		0.58
ClinPred		0.11	T
GERP RS		3.9
Varity_R		0.60
gMVP		0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: -11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs542486536; hg19: chr1-24124651;