chr9-128945710-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_014908.4(DOLK):c.1594C>T(p.Leu532Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0000186 in 1,614,114 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L532L) has been classified as Likely benign.
Frequency
Consequence
NM_014908.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DOLK | NM_014908.4 | c.1594C>T | p.Leu532Phe | missense_variant | 1/1 | ENST00000372586.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DOLK | ENST00000372586.4 | c.1594C>T | p.Leu532Phe | missense_variant | 1/1 | NM_014908.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152112Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251488Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135918
GnomAD4 exome AF: 0.0000178 AC: 26AN: 1461884Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727242
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74440
ClinVar
Submissions by phenotype
DK1-congenital disorder of glycosylation Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 03, 2023 | This sequence change replaces leucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 532 of the DOLK protein (p.Leu532Phe). This variant is present in population databases (rs140350881, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with DOLK-related conditions. ClinVar contains an entry for this variant (Variation ID: 1440881). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DOLK protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 11, 2021 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 19, 2022 | The p.L532F variant (also known as c.1594C>T), located in coding exon 1 of the DOLK gene, results from a C to T substitution at nucleotide position 1594. The leucine at codon 532 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at