rs760941

chr1-23796496-C-Gchr1-23796496-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001008216.2(GALE):c.873+13G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000945 in 1,392,538 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 14)
  • Exomes 𝑓: 0.00092 (1 hom.)
• Consequence: GALE NM_001008216.2 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.798

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 1-23796496-C-G is Benign according to our data. Variant chr1-23796496-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 402890.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00127 (138/108690) while in subpopulation NFE AF= 0.00185 (97/52450). AF 95% confidence interval is 0.00155. There are 2 homozygotes in gnomad4. There are 69 alleles in male gnomad4 subpopulation. Median coverage is 14. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GALE	NM_001008216.2	c.873+13G>C		intron_variant		ENST00000617979.5
GALE	NM_000403.4	c.873+13G>C		intron_variant
GALE	NM_001127621.2	c.873+13G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALE	ENST00000617979.5	c.873+13G>C		intron_variant		1	NM_001008216.2	P1

Frequencies

GnomAD3 genomes AF: 0.00126 AC: 137 AN: 108624 Hom.: 2 Cov.: 14

Gnomad AFR AF: 0.000664

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000634

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.000805

Gnomad SAS AF: 0.00115

Gnomad FIN AF: 0.000417

Gnomad MID AF: 0.00410

Gnomad NFE AF: 0.00185

Gnomad OTH AF: 0.000694

GnomAD3 exomes AF: 0.00156 AC: 350 AN: 224046 Hom.: 0 AF XY: 0.00139 AC XY: 170 AN XY: 122282

Gnomad AFR exome AF: 0.000926

Gnomad AMR exome AF: 0.000851

Gnomad ASJ exome AF: 0.000637

Gnomad EAS exome AF: 0.00145

Gnomad SAS exome AF: 0.000986

Gnomad FIN exome AF: 0.00292

Gnomad NFE exome AF: 0.00193

Gnomad OTH exome AF: 0.000906

GnomAD4 exome AF: 0.000918 AC: 1178 AN: 1283848 Hom.: 1 Cov.: 36 AF XY: 0.000887 AC XY: 568 AN XY: 640066

Gnomad4 AFR exome AF: 0.000184

Gnomad4 AMR exome AF: 0.000896

Gnomad4 ASJ exome AF: 0.000132

Gnomad4 EAS exome AF: 0.000641

Gnomad4 SAS exome AF: 0.000531

Gnomad4 FIN exome AF: 0.00158

Gnomad4 NFE exome AF: 0.000962

Gnomad4 OTH exome AF: 0.000961

GnomAD4 genome AF: 0.00127 AC: 138 AN: 108690 Hom.: 2 Cov.: 14 AF XY: 0.00131 AC XY: 69 AN XY: 52594

Gnomad4 AFR AF: 0.000701

Gnomad4 AMR AF: 0.000633

Gnomad4 ASJ AF: 0.00145

Gnomad4 EAS AF: 0.000807

Gnomad4 SAS AF: 0.00115

Gnomad4 FIN AF: 0.000417

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.000689

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

UDPglucose-4-epimerase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Same variant as above. Gene associated with epimerase deficiency galactosemia - Infants with the profound generalized form who are on a diet containing galactose/lactose manifest hypotonia, poor feeding, vomiting, weight loss, jaundice, hepatomegaly, liver dysfunction, aminoaciduria, and cataracts. Frequency and location of variant suggest benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.78
Dann	Benign	0.68

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: rs760941; hg19: chr1-24122986; COSMIC: COSV65720422; COSMIC: COSV65720422;