rs144647383
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_017636.4(TRPM4):āc.3405A>Cā(p.Ala1135=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000779 in 1,613,956 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.0042 ( 8 hom., cov: 31)
Exomes š: 0.00042 ( 8 hom. )
Consequence
TRPM4
NM_017636.4 synonymous
NM_017636.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -3.86
Genes affected
TRPM4 (HGNC:17993): (transient receptor potential cation channel subfamily M member 4) The protein encoded by this gene is a calcium-activated nonselective ion channel that mediates transport of monovalent cations across membranes, thereby depolarizing the membrane. The activity of the encoded protein increases with increasing intracellular calcium concentration, but this channel does not transport calcium. [provided by RefSeq, Mar 2016]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.89).
BP6
Variant 19-49210786-A-C is Benign according to our data. Variant chr19-49210786-A-C is described in ClinVar as [Benign]. Clinvar id is 241178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-49210786-A-C is described in Lovd as [Benign].
BP7
Synonymous conserved (PhyloP=-3.86 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0042 (640/152290) while in subpopulation AFR AF= 0.0147 (612/41572). AF 95% confidence interval is 0.0138. There are 8 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 640 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TRPM4 | NM_017636.4 | c.3405A>C | p.Ala1135= | synonymous_variant | 22/25 | ENST00000252826.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TRPM4 | ENST00000252826.10 | c.3405A>C | p.Ala1135= | synonymous_variant | 22/25 | 1 | NM_017636.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00421 AC: 640AN: 152172Hom.: 8 Cov.: 31
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GnomAD3 exomes AF: 0.00108 AC: 270AN: 249632Hom.: 7 AF XY: 0.000711 AC XY: 96AN XY: 134980
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GnomAD4 exome AF: 0.000422 AC: 617AN: 1461666Hom.: 8 Cov.: 34 AF XY: 0.000337 AC XY: 245AN XY: 727098
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GnomAD4 genome AF: 0.00420 AC: 640AN: 152290Hom.: 8 Cov.: 31 AF XY: 0.00403 AC XY: 300AN XY: 74458
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ClinVar
Significance: Benign
Submissions summary: Benign:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 09, 2024 | Variant summary: TRPM4 c.3405A>C results in a synonymous change. Several computational tools predict a significant impact on normal splicing: One predict the variant strengthens a cryptic 3' acceptor site. Two predict the variant creates the cryptic 3' acceptor site. One predict the variant no significant impact on splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0011 in 249632 control chromosomes in the gnomAD database, including 7 homozygotes. The observed variant frequency is approximately 432 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 benign. To our knowledge, no occurrence of c.3405A>C in individuals affected with Progressive Familial Heart Block Type 1B and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 241178). Based on the evidence outlined above, the variant was classified as benign. - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 13, 2017 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Dec 27, 2019 | - - |
Progressive familial heart block type IB Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 15, 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
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at