17-75758304-A-AC

Position:

• chr17-75758304-A-AC

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_000154.2(GALK1):​c.1012_1013insG​(p.Val338GlyfsTer65) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GALK1 NM_000154.2 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 5.70

Genes affected

GALK1 (HGNC:4118): (galactokinase 1) Galactokinase is a major enzyme for the metabolism of galactose and its deficiency causes congenital cataracts during infancy and presenile cataracts in the adult population. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.142 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-75758304-A-AC is Pathogenic according to our data. Variant chr17-75758304-A-AC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 551344.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GALK1	NM_000154.2	c.1012_1013insG	p.Val338GlyfsTer65	frameshift_variant	7/8	ENST00000588479.6	NP_000145.1
GALK1	NM_001381985.1	c.1012_1013insG	p.Val338GlyfsTer99	frameshift_variant	7/9		NP_001368914.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GALK1	ENST00000588479.6	c.1012_1013insG	p.Val338GlyfsTer65	frameshift_variant	7/8	1	NM_000154.2	ENSP00000465930	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Deficiency of galactokinase Pathogenic:1 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	May 12, 2021	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the GALK1 protein. Other variant(s) that disrupt this region (p.Pro362Trpfs*37) have been determined to be pathogenic (Invitae). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with GALK1-related conditions (PMID: 10790206). ClinVar contains an entry for this variant (Variation ID: 551344). This variant is not present in population databases (ExAC no frequency). This sequence change results in a frameshift in the GALK1 gene (p.Val338Glyfs*65). While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 55 amino acid(s) of the GALK1 protein and extend the protein by 9 additional amino acid residues. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Oct 09, 2017	- -

Computational scores

Source: dbNSFP v4.3

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: rs1555747776; hg19: chr17-73754385;