rs767329054
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000154.2(GALK1):c.410del(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 Likely 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
NM_000154.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.54
Genes affected
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 552633.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GALK1 | NM_000154.2 | c.410del | p.Gly137ValfsTer27 | frameshift_variant | 3/8 | ENST00000588479.6 | |
GALK1 | NM_001381985.1 | c.410del | p.Gly137ValfsTer27 | frameshift_variant | 3/9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GALK1 | ENST00000588479.6 | c.410del | p.Gly137ValfsTer27 | frameshift_variant | 3/8 | 1 | NM_000154.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome AF: 0.00000274 AC: 4AN: 1460956Hom.: 0 Cov.: 37 AF XY: 0.00000275 AC XY: 2AN XY: 726756
GnomAD4 exome
AF:
AC:
4
AN:
1460956
Hom.:
Cov.:
37
AF XY:
AC XY:
2
AN XY:
726756
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
Bravo
AF:
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Deficiency of galactokinase Pathogenic:6
Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 17, 2018 | The p.Gly137ValfsX27 variant in GALK1 has been reported in the homozygous state in 6 affected members of one Pakistani family with early-onset cataracts (Yasmeen 2010). It was absent from large population studies. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 137 and leads to a premature termination codon 27 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. In summary, this variant meets criteria to be classified as pathogenic for galactokinase deficiency in an autosomal recessive manner. ACMG/AMP criteria applied: PVS1_Strong, PP1_Strong, PM2, PM3_Supporting. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 27, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change creates a premature translational stop signal (p.Gly137Valfs*27) in the GALK1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GALK1 are known to be pathogenic (PMID: 7670469, 10790206). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with GALK1-related conditions (PMID: 10570908, 20405025). ClinVar contains an entry for this variant (Variation ID: 552633). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Frameshift: predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). The variant has been reported at least twice as pathogenic/likely pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000552633, PMID:10570908). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 13, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 06, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jul 01, 2023 | GALK1: PVS1, PM2, PM3, PP4 - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at