Genetic Variant NM_001008216.2:c.770A>T (chr1-23796722-T-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_001008216.2(GALE):c.770A>T(p.Lys257Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. K257R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

GALE
NM_001008216.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.35

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

galactose epimerase deficiency
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

GALE links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.842

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008216.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GALE	NM_001008216.2	MANE Select	c.770A>T	p.Lys257Met	missense	Exon 9 of 12	NP_001008217.1	A0A384NL38
GALE	NM_000403.4		c.770A>T	p.Lys257Met	missense	Exon 9 of 12	NP_000394.2	Q14376-1
GALE	NM_001127621.2		c.770A>T	p.Lys257Met	missense	Exon 8 of 11	NP_001121093.1	A0A384NL38

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GALE	ENST00000617979.5	TSL:1 MANE Select	c.770A>T	p.Lys257Met	missense	Exon 9 of 12	ENSP00000483375.1	Q14376-1
GALE	ENST00000374497.7	TSL:1	c.770A>T	p.Lys257Met	missense	Exon 9 of 12	ENSP00000363621.3	Q14376-1
GALE	ENST00000854948.1		c.770A>T	p.Lys257Met	missense	Exon 8 of 11	ENSP00000525007.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.92

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Pathogenic

0.34

MetaRNN

Pathogenic

0.84

MetaSVM

Pathogenic

0.95

MutationAssessor

Uncertain

2.7

PhyloP100

7.3

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.7

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.022

Polyphen

0.97

Vest4

0.86

MutPred

0.63

Gain of helix (P = 0.0696)

MVP

0.96

MPC

0.71

ClinPred

1.0

GERP RS

5.7

PromoterAI

-0.16

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.8

Varity_R

0.95

gMVP

0.81

Mutation Taster

=14/86

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over