rs754625848
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2
The NM_017636.4(TRPM4):c.247dup(p.Ala83GlyfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000771 in 1,607,484 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T81T) has been classified as Benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_017636.4 frameshift
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -4 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TRPM4 | NM_017636.4 | c.247dup | p.Ala83GlyfsTer13 | frameshift_variant | 3/25 | ENST00000252826.10 | NP_060106.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TRPM4 | ENST00000252826.10 | c.247dup | p.Ala83GlyfsTer13 | frameshift_variant | 3/25 | 1 | NM_017636.4 | ENSP00000252826 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000657 AC: 10AN: 152150Hom.: 0 Cov.: 31
GnomAD3 exomes AF: 0.0000426 AC: 10AN: 234470Hom.: 0 AF XY: 0.0000627 AC XY: 8AN XY: 127608
GnomAD4 exome AF: 0.0000783 AC: 114AN: 1455216Hom.: 0 Cov.: 31 AF XY: 0.0000843 AC XY: 61AN XY: 723340
GnomAD4 genome AF: 0.0000657 AC: 10AN: 152268Hom.: 0 Cov.: 31 AF XY: 0.0000940 AC XY: 7AN XY: 74452
ClinVar
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | AiLife Diagnostics, AiLife Diagnostics | Nov 18, 2021 | - - |
Progressive familial heart block type IB Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Nov 14, 2023 | This sequence change creates a premature translational stop signal (p.Ala83Glyfs*13) in the TRPM4 gene. It is expected to result in an absent or disrupted protein product. However, the current clinical and genetic evidence is not sufficient to establish whether loss-of-function variants in TRPM4 cause disease. This variant is present in population databases (rs754625848, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with sudden infant death syndrome, atrial fibrillation and dilated cardiomyopathy (PMID: 28074886, 34495297, 35288587). ClinVar contains an entry for this variant (Variation ID: 518703). 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. - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 24, 2023 | The c.247dupG variant, located in coding exon 3 of the TRPM4 gene, results from a duplication of one at nucleotide position 247, causing a translational frameshift with a predicted alternate stop codon (p.A83Gfs*13). This alteration was found by whole exome sequencing in one case of sudden infant death syndrome (Neubauer J et al. Eur. J. Hum. Genet., 2017 Apr;25:404-409). This alteration has also been seen in an atrial fibrillation cohort and a cardiomyopathy cohort (Yoneda ZT et al. JAMA Cardiol, 2021 Dec;6:1371-1379; Lesurf R et al. NPJ Genom Med, 2022 Mar;7:18). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. However, loss of function of TRPM4 has not been clearly established as a mechanism of disease. 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