rs3729836
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000363.5(TNNI3):c.25-8T>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,595,860 control chromosomes in the GnomAD database, including 61,446 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000363.5 splice_region, intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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TNNI3 | ENST00000344887.10 | c.25-8T>A | splice_region_variant, intron_variant | Intron 2 of 7 | 1 | NM_000363.5 | ENSP00000341838.5 | |||
ENSG00000267110 | ENST00000587871.1 | n.*132-13T>A | intron_variant | Intron 5 of 8 | 5 | ENSP00000473050.1 |
Frequencies
GnomAD3 genomes AF: 0.353 AC: 53463AN: 151578Hom.: 11930 Cov.: 31
GnomAD3 exomes AF: 0.316 AC: 68587AN: 216832Hom.: 13019 AF XY: 0.309 AC XY: 36195AN XY: 117204
GnomAD4 exome AF: 0.242 AC: 348815AN: 1444164Hom.: 49476 Cov.: 35 AF XY: 0.245 AC XY: 175355AN XY: 716598
GnomAD4 genome AF: 0.353 AC: 53569AN: 151696Hom.: 11970 Cov.: 31 AF XY: 0.355 AC XY: 26325AN XY: 74090
ClinVar
Submissions by phenotype
not specified Benign:9
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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. -
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Note this variant was found in clinical genetic testing performed by one or more labs who may also submit to ClinVar. Thus any internal case data may overlap with the internal case data of other labs. The interpretation reviewed below is that of the Stanford Center for Inherited Cardiovascular Disease. c.25-8T>A. At the time of testing, the testing lab classified this as a variant of unknown significance. However, a review of dbSNP reveals that this variant is common in general populations samples (rs3729836). It is frequently seen in NHLBI Exome Sequencing Project dataset, which currently includes variant calls on ~6,500 Caucasian and African American individuals (as of 7/15/13). It is reported in 3,907/12,358 alleles (as of 7/15/13) -
Cardiomyopathy, familial restrictive, 1 Benign:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Cardiomyopathy Benign:2
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Hypertrophic cardiomyopathy 7 Benign:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Hypertrophic cardiomyopathy Benign:2
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Dilated cardiomyopathy 2A Benign:2
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This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Familial Hypertrophic Cardiomyopathy with Wolff-Parkinson-White Syndrome Benign:1
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Primary ciliary dyskinesia Benign:1
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Dilated Cardiomyopathy, Recessive Benign:1
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not provided Benign:1
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Familial restrictive cardiomyopathy Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at