1-23796503-G-T

Variant names:

• chr1-23796503-G-T
• rs1553130228
• NM_001008216.2:c.873+6C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001008216.2(GALE):​c.873+6C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000723 in 138,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000072 (0 hom., cov: 31)
  • Exomes 𝑓: 9.9e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GALE NM_001008216.2 splice_region, intron
• Scores: Splicing: ADA: 0.0004816
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.626
• Publications: 0 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GALE	NM_001008216.2	c.873+6C>A		splice_region_variant, intron_variant	Intron 10 of 11	ENST00000617979.5	NP_001008217.1
GALE	NM_000403.4	c.873+6C>A		splice_region_variant, intron_variant	Intron 10 of 11		NP_000394.2
GALE	NM_001127621.2	c.873+6C>A		splice_region_variant, intron_variant	Intron 9 of 10		NP_001121093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GALE	ENST00000617979.5	c.873+6C>A		splice_region_variant, intron_variant	Intron 10 of 11	1	NM_001008216.2	ENSP00000483375.1

Frequencies

GnomAD3 genomes AF: 0.00000723 AC: 1 AN: 138220 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000260

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.86e-7 AC: 1 AN: 1013880 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 513244

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 23478

American (AMR) AF: 0.00 AC: 0 AN: 38916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17814

East Asian (EAS) AF: 0.00 AC: 0 AN: 23294

South Asian (SAS) AF: 0.00 AC: 0 AN: 78450

European-Finnish (FIN) AF: 0.0000265 AC: 1 AN: 37756

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2840

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 751548

Other (OTH) AF: 0.00 AC: 0 AN: 39784

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000723 AC: 1 AN: 138220 Hom.: 0 Cov.: 31 AF XY: 0.0000150 AC XY: 1 AN XY: 66760

African (AFR) AF: 0.0000260 AC: 1 AN: 38492

American (AMR) AF: 0.00 AC: 0 AN: 14048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3254

East Asian (EAS) AF: 0.00 AC: 0 AN: 4034

South Asian (SAS) AF: 0.00 AC: 0 AN: 3710

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63300

Other (OTH) AF: 0.00 AC: 0 AN: 1950

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	7.9
DANN	Benign	0.81
PhyloP100		0.63
PromoterAI		-0.080	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00048
dbscSNV1_RF	Benign	0.012
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

Other links and lift over

dbSNP: rs1553130228; hg19: chr1-24122993; COSMIC: COSV65720972; COSMIC: COSV65720972;