rs137853860

Positions:

• chr1-23796777-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_Very_Strong

The NM_001008216.2(GALE):​c.715C>T​(p.Arg239Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000869 in 1,610,332 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GALE NM_001008216.2 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 1.74

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity GALE_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 1-23796777-G-A is Pathogenic according to our data. Variant chr1-23796777-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 21172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALE	NM_001008216.2	c.715C>T	p.Arg239Trp	missense_variant	9/12	ENST00000617979.5	NP_001008217.1
GALE	NM_000403.4	c.715C>T	p.Arg239Trp	missense_variant	9/12		NP_000394.2
GALE	NM_001127621.2	c.715C>T	p.Arg239Trp	missense_variant	8/11		NP_001121093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5	c.715C>T	p.Arg239Trp	missense_variant	9/12	1	NM_001008216.2	ENSP00000483375.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000164 AC: 4 AN: 243976 Hom.: 0 AF XY: 0.0000228 AC XY: 3 AN XY: 131626

Gnomad AFR exome AF: 0.0000649

Gnomad AMR exome AF: 0.0000296

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000908

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1458070 Hom.: 0 Cov.: 35 AF XY: 0.0000124 AC XY: 9 AN XY: 724898

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000226

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74450

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
not provided, no classification provided	literature only	GeneReviews	-	Account for 67% of alleles reported in a cohort of asymptomatic Koreans with peripheral epimerase deficiency galactosemia -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 05, 2023	Variant summary: GALE c.715C>T (p.Arg239Trp) results in a non-conservative amino acid change located in the NAD(P)-binding domain (IPR016040) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. This is supported by molecular dynamics, residue network analysis, and cross-correlation matrix based computational strategies (Kumar_2019) supporting a critical amino acid residue essential for UDP-galactose 4-epimerase enzyme function. The variant allele was found at a frequency of 1.6e-05 in 243976 control chromosomes. c.715C>T has been reported in the literature as a biallelic genotype in individuals affected with UDPglucose-4-Epimerase Deficiency (example Park_2005). At least one publication reports experimental evidence evaluating an impact on protein function (Bang_2009). The most pronounced variant effect results in no detectable enzyme activity when expressed in GALE-null ldlD cells. Also unlike wild-type, this variant was not able to rescue galactose-sensitive cell proliferation when stably expressed in ldlD cells. The following publications have been ascertained in the context of this evaluation (PMID: 19250319, 33555556, 16301867, 30247636). One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 28, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.92	D;D;D;T;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	5.2	H;H;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.9	.;D;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;.;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.98
MutPred		0.97		Loss of disorder (P = 0.0283);Loss of disorder (P = 0.0283);.;.;.;
MVP		0.99
MPC		0.63
ClinPred		1.0	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.98
gMVP		0.93

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

LitVar

Other links and lift over

dbSNP: rs137853860; hg19: chr1-24123267;