1-23796006-AC-GT

Variant names:

• chr1-23796006-AC-GT
• NM_001008216.2:c.989_990delGTinsAC
• GALE p.Cys330Tyr

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP2

The NM_001008216.2(GALE):​c.989_990delGTinsAC​(p.Cys330Tyr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type MNV, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GALE NM_001008216.2 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.56
• 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008216.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALE	NM_001008216.2	MANE Select	c.989_990delGTinsAC	p.Cys330Tyr	missense splice_region	N/A	NP_001008217.1	A0A384NL38
	GALE	NM_000403.4		c.989_990delGTinsAC	p.Cys330Tyr	missense splice_region	N/A	NP_000394.2	Q14376-1
	GALE	NM_001127621.2		c.989_990delGTinsAC	p.Cys330Tyr	missense splice_region	N/A	NP_001121093.1	A0A384NL38

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALE	ENST00000617979.5	TSL:1 MANE Select	c.989_990delGTinsAC	p.Cys330Tyr	missense splice_region	N/A	ENSP00000483375.1	Q14376-1
	GALE	ENST00000374497.7	TSL:1	c.989_990delGTinsAC	p.Cys330Tyr	missense splice_region	N/A	ENSP00000363621.3	Q14376-1
	GALE	ENST00000854948.1		c.989_990delGTinsAC	p.Cys330Tyr	missense splice_region	N/A	ENSP00000525007.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		5.6

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-24122496;