rs121908045

Variant names:

• chr1-23797128-A-G
• rs121908045
• NM_001008216.2:c.548T>C

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_001008216.2(GALE):​c.548T>C​(p.Leu183Pro) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALE NM_001008216.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.85
• Publications: 10 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: Likely_pathogenic. The variant received 9 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, 0.99
• PP5: Variant 1-23797128-A-G is Pathogenic according to our data. Variant chr1-23797128-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3675.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALE	NM_001008216.2	c.548T>C	p.Leu183Pro	missense_variant	Exon 7 of 12	ENST00000617979.5	NP_001008217.1
GALE	NM_000403.4	c.548T>C	p.Leu183Pro	missense_variant	Exon 7 of 12		NP_000394.2
GALE	NM_001127621.2	c.548T>C	p.Leu183Pro	missense_variant	Exon 6 of 11		NP_001121093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5	c.548T>C	p.Leu183Pro	missense_variant	Exon 7 of 12	1	NM_001008216.2	ENSP00000483375.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000411 AC: 1 AN: 243278 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000887 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

UDPglucose-4-epimerase deficiency Pathogenic:1

Sep 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

UDPglucose-4-epimerase deficiency;C5935599:Thrombocytopenia 13, syndromic Pathogenic:1

Jan 20, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.49
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D;D;T;.;D;D
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;.;D;D;.;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	5.1	H;H;.;.;.;.
PhyloP100		8.9
PrimateAI	Pathogenic	0.80	T
PROVEAN	Pathogenic	-6.9	.;D;D;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	.;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;.;D;.;D
Polyphen		1.0	D;D;.;.;.;.
Vest4		0.99
MutPred		0.96		Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);.;.;Loss of sheet (P = 0.0126);Loss of sheet (P = 0.0126);
MVP		0.97
MPC		0.79
ClinPred		1.0	D
GERP RS		5.3
PromoterAI		-0.039	Neutral
Varity_R		0.99
gMVP		0.97
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs121908045; hg19: chr1-24123618;