rs28940883

Variant names:

• chr1-23798160-T-A
• rs28940883
• NM_001008216.2:c.308A>T

Your query was ambiguous. Multiple possible variants found:

• chr1-23798160-T-A
• chr1-23798160-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001008216.2(GALE):​c.308A>T​(p.Asp103Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D103Y) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALE NM_001008216.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALE	NM_001008216.2	c.308A>T	p.Asp103Val	missense_variant	Exon 5 of 12	ENST00000617979.5	NP_001008217.1
GALE	NM_000403.4	c.308A>T	p.Asp103Val	missense_variant	Exon 5 of 12		NP_000394.2
GALE	NM_001127621.2	c.308A>T	p.Asp103Val	missense_variant	Exon 4 of 11		NP_001121093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5	c.308A>T	p.Asp103Val	missense_variant	Exon 5 of 12	1	NM_001008216.2	ENSP00000483375.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D;D;T;.;D;D
Eigen	Benign	-0.013
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Pathogenic	0.99	D;.;D;D;.;D
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.39	T;T;T;T;T;T
MetaSVM	Uncertain	0.38	D
MutationAssessor	Benign	1.2	L;L;.;.;.;.
PhyloP100		2.0
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.6	.;N;N;N;N;N
REVEL	Uncertain	0.63
Sift	Benign	0.056	.;T;D;D;T;T
Sift4G	Uncertain	0.057	T;T;.;D;.;T
Polyphen		0.098	B;B;.;.;.;.
Vest4		0.63
MutPred		0.56		Gain of methylation at K100 (P = 0.0405);Gain of methylation at K100 (P = 0.0405);.;.;Gain of methylation at K100 (P = 0.0405);Gain of methylation at K100 (P = 0.0405);
MVP		0.90
MPC		0.30
ClinPred		0.44	T
GERP RS		4.8
Varity_R		0.57
gMVP		0.73
Mutation Taster		=81/19	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.21		Position offset: -10

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

Other links and lift over

dbSNP: rs28940883; hg19: chr1-24124650;