rs767329054

Variant names:

• chr17-75763384-AC-A
• rs767329054
• NM_000154.2:c.410delG

Your query was ambiguous. Multiple possible variants found:

• chr17-75763384-AC-A
• chr17-75763384-AC-ACC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000154.2(GALK1):​c.410delG​(p.Gly137ValfsTer27) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,956 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GALK1 NM_000154.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.54
• Publications: 3 publications found

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]

GALK1 Gene-Disease associations (from GenCC):

• galactokinase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Myriad Women’s Health, Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 17-75763384-AC-A is Pathogenic according to our data. Variant chr17-75763384-AC-A is described in ClinVar as Pathogenic. ClinVar VariationId is 552633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000154.2. 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
	GALK1	NM_000154.2	MANE Select	c.410delG	p.Gly137ValfsTer27	frameshift	Exon 3 of 8	NP_000145.1	P51570
	GALK1	NM_001381985.1		c.410delG	p.Gly137ValfsTer27	frameshift	Exon 3 of 9	NP_001368914.1	P51570

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GALK1	ENST00000588479.6	TSL:1 MANE Select	c.410delG	p.Gly137ValfsTer27	frameshift	Exon 3 of 8	ENSP00000465930.1	P51570
	GALK1	ENST00000586244.1	TSL:1	n.*134delG		non_coding_transcript_exon	Exon 4 of 4	ENSP00000468288.1	K7ERJ9
	GALK1	ENST00000586244.1	TSL:1	n.*134delG		3_prime_UTR	Exon 4 of 4	ENSP00000468288.1	K7ERJ9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460956 Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2 AN XY: 726756

⚠️ 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: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26092

East Asian (EAS) AF: 0.00 AC: 0 AN: 39664

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86118

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53168

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111754

Other (OTH) AF: 0.00 AC: 0 AN: 60354

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000173310), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Deficiency of galactokinase (6)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.5
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs767329054; hg19: chr17-73759465; COSMIC: COSV56690104; COSMIC: COSV56690104;