chr19-49200723-G-A
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2
The NM_017636.4(TRPM4):c.2891G>A(p.Arg964His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,930 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R964S) has been classified as Uncertain significance.
Frequency
Consequence
NM_017636.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPM4 | NM_017636.4 | c.2891G>A | p.Arg964His | missense_variant | 19/25 | ENST00000252826.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPM4 | ENST00000252826.10 | c.2891G>A | p.Arg964His | missense_variant | 19/25 | 1 | NM_017636.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251192Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135840
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461830Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5AN XY: 727216
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152100Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74294
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jul 31, 2017 | The R964H variant of uncertain significance in the TRPM4 gene has not been published as pathogenic or been reported as benign to our knowledge. R964H is not observed at a significant frequency in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R964H variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. However, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. - |
Progressive familial heart block type IB Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 10, 2022 | 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 449706). This variant has not been reported in the literature in individuals affected with TRPM4-related conditions. This variant is present in population databases (rs372848098, gnomAD 0.003%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 964 of the TRPM4 protein (p.Arg964His). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at