19-49182771-CCAAAGCCCCAGCCCTAAAAGGGGGAGCTGCGGAGCT-C
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4BP6BS1BS2
The NM_017636.4(TRPM4):c.1459_1494del(p.Lys487_Leu498del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,614,016 control chromosomes in the GnomAD database, including 138 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T486T) has been classified as Likely benign.
Frequency
Consequence
NM_017636.4 inframe_deletion
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPM4 | NM_017636.4 | c.1459_1494del | p.Lys487_Leu498del | inframe_deletion | 11/25 | ENST00000252826.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPM4 | ENST00000252826.10 | c.1459_1494del | p.Lys487_Leu498del | inframe_deletion | 11/25 | 1 | NM_017636.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00730 AC: 1111AN: 152242Hom.: 5 Cov.: 32
GnomAD3 exomes AF: 0.00784 AC: 1944AN: 247918Hom.: 10 AF XY: 0.00792 AC XY: 1066AN XY: 134562
GnomAD4 exome AF: 0.0117 AC: 17131AN: 1461656Hom.: 133 AF XY: 0.0116 AC XY: 8425AN XY: 727134
GnomAD4 genome AF: 0.00729 AC: 1110AN: 152360Hom.: 5 Cov.: 32 AF XY: 0.00695 AC XY: 518AN XY: 74508
ClinVar
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 27, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 03, 2023 | - - |
Brugada syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Center For Human Genetics And Laboratory Diagnostics, Dr. Klein, Dr. Rost And Colleagues | Nov 16, 2016 | - - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 21, 2023 | Variant summary: TRPM4 c.1459_1494del36 (p.Lys487_Leu498del) results in an in-frame deletion that is predicted to remove twelve amino acids from the encoded protein. The variant allele was found at a frequency of 0.0078 in 247918 control chromosomes, predominantly at a frequency of 0.011 within the Non-Finnish European subpopulation in the gnomAD database, including 3 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 4399.99 fold of the estimated maximal expected allele frequency for a pathogenic variant in TRPM4 causing Progressive Familial Heart Block Type 1B phenotype (2.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1459_1494del36 has been reported in the literature as a polymorphism, and in a patient with a pathogenic variant explaining their phenotype (Syam_2016, Neubauer_2021). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 27207958, 33895855). Six submitters have cited clinical-significance assessments for this variant to ClinVar after 2014: five classified the variant as likely benign while one classified as VUS. Based on the evidence outlined above, the variant was classified as benign. - |
Cardiomyopathy Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego | Sep 08, 2017 | - - |
TRPM4-related disorder Benign:1
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 17, 2020 | This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Progressive familial heart block type IB Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 08, 2016 | This alteration is classified as 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at