1-23795620-T-TTTA

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_001008216.2(GALE):c.*328_*329insTAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 458,614 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (12 hom.)
• Consequence: GALE NM_001008216.2 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00465 (709/152334) while in subpopulation NFE AF= 0.00707 (481/68036). AF 95% confidence interval is 0.00655. There are 2 homozygotes in gnomad4. There are 326 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• 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.*328_*329insTAA		3_prime_UTR_variant	12/12	ENST00000617979.5
GALE	NM_000403.4	c.*328_*329insTAA		3_prime_UTR_variant	12/12
GALE	NM_001127621.2	c.*328_*329insTAA		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GALE	ENST00000617979.5	c.*328_*329insTAA		3_prime_UTR_variant	12/12	1	NM_001008216.2	P1

Frequencies

GnomAD3 genomes AF: 0.00465 AC: 708 AN: 152216 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00137

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.00524

Gnomad ASJ AF: 0.00836

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00330

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00707

Gnomad OTH AF: 0.00669

GnomAD4 exome AF: 0.00501 AC: 1533 AN: 306280 Hom.: 12 Cov.: 0 AF XY: 0.00472 AC XY: 758 AN XY: 160498

Gnomad4 AFR exome AF: 0.000952

Gnomad4 AMR exome AF: 0.00522

Gnomad4 ASJ exome AF: 0.00839

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00185

Gnomad4 FIN exome AF: 0.00194

Gnomad4 NFE exome AF: 0.00629

Gnomad4 OTH exome AF: 0.00616

GnomAD4 genome AF: 0.00465 AC: 709 AN: 152334 Hom.: 2 Cov.: 32 AF XY: 0.00438 AC XY: 326 AN XY: 74474

Gnomad4 AFR AF: 0.00137

Gnomad4 AMR AF: 0.00523

Gnomad4 ASJ AF: 0.00836

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00330

Gnomad4 NFE AF: 0.00707

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00583 Hom.: 0

Bravo AF: 0.00465

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

UDPglucose-4-epimerase deficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs557214506; hg19: chr1-24122110;