chr15-84859366-G-A
Variant summary
Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting
The NM_020778.5(ALPK3):c.3941G>A(p.Arg1314His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1314C) has been classified as Likely benign.
Frequency
Consequence
NM_020778.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Our verdict: Likely_benign. The variant received -5 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32 show subpopulations
GnomAD2 exomes AF: 0.000195 AC: 49AN: 251278 AF XY: 0.000125 show subpopulations
GnomAD4 exome AF: 0.0000410 AC: 60AN: 1461844Hom.: 0 Cov.: 32 AF XY: 0.0000344 AC XY: 25AN XY: 727224 show subpopulations
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152164Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3AN XY: 74322 show subpopulations
ClinVar
Submissions by phenotype
not provided Uncertain:2
This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1516 of the ALPK3 protein (p.Arg1516His). This variant is present in population databases (rs746125587, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with ALPK3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1510476). 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 ALPK3 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. -
Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -
Cardiovascular phenotype Uncertain:1Benign:1
This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
PM2;BP1;BP4 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at