rs151205002
Variant summary
Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2
The NM_017636.4(TRPM4):c.856A>G(p.Thr286Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,613,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/25 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. 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. T286M) has been classified as Uncertain significance.
Frequency
Consequence
NM_017636.4 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPM4 | NM_017636.4 | c.856A>G | p.Thr286Ala | missense_variant, splice_region_variant | 7/25 | ENST00000252826.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPM4 | ENST00000252826.10 | c.856A>G | p.Thr286Ala | missense_variant, splice_region_variant | 7/25 | 1 | NM_017636.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000138 AC: 21AN: 151720Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000191 AC: 48AN: 251420Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135900
GnomAD4 exome AF: 0.000122 AC: 179AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.000140 AC XY: 102AN XY: 727242
GnomAD4 genome ? AF: 0.000138 AC: 21AN: 151838Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4AN XY: 74212
ClinVar
Submissions by phenotype
Progressive familial heart block type IB Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 04, 2024 | This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 286 of the TRPM4 protein (p.Thr286Ala). This variant is present in population databases (rs151205002, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TRPM4-related conditions. ClinVar contains an entry for this variant (Variation ID: 578268). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Aug 29, 2023 | Identified in a patient with Sudden Infant Death syndrome (SIDS) who also harbored the c.1690_1692dupCTT variant in the TRPM4 gene (Campuzano et al., 2018); At the protein level, in silico analysis supports that this missense variant does not alter protein structure/function; In silico analysis is inconclusive as to whether the variant alters gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown.; This variant is associated with the following publications: (PMID: 30086531) - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | May 11, 2023 | The p.T286A variant (also known as c.856A>G), located in coding exon 7 of the TRPM4 gene, results from an A to G substitution at nucleotide position 856. The threonine at codon 286 is replaced by alanine, an amino acid with similar properties. This alteration has been reported in a sudden infant death syndrome (SIDS) cohort (Campuzano O et al. Forensic Sci Int Genet, 2018 Nov;37:54-63). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated 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