NM_014908.4:c.1067G>A
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_014908.4(DOLK):c.1067G>A(p.Arg356Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000991 in 1,613,936 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_014908.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -1 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DOLK | NM_014908.4 | c.1067G>A | p.Arg356Gln | missense_variant | Exon 1 of 1 | ENST00000372586.4 | NP_055723.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000460 AC: 7AN: 152102Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251336Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135838
GnomAD4 exome AF: 0.00000616 AC: 9AN: 1461834Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4AN XY: 727214
GnomAD4 genome AF: 0.0000460 AC: 7AN: 152102Hom.: 0 Cov.: 32 AF XY: 0.0000673 AC XY: 5AN XY: 74278
ClinVar
Submissions by phenotype
DK1-congenital disorder of glycosylation Uncertain:2
This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 356 of the DOLK protein (p.Arg356Gln). This variant is present in population databases (rs199535796, gnomAD 0.01%). 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: 464195). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt DOLK protein function with a negative predictive value of 80%. 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. -
The p.Arg356Gln variant in the DOLK gene has not been previously reported in association with disease.This variant has been identified in 3/24958 African American chromosomes (6/282732 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant is present in ClinVar (Variation ID: 464195). Computational tools predict that this variant is neither deleterious nor benign; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Arg356Gln variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: PM2] -
not provided Uncertain:1
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Cardiovascular phenotype Uncertain:1
The p.R356Q variant (also known as c.1067G>A), located in coding exon 1 of the DOLK gene, results from a G to A substitution at nucleotide position 1067. The arginine at codon 356 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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