chr11-47332891-C-T
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP4_StrongBP6_Very_StrongBS2
The NM_000256.3(MYBPC3):c.3413G>A(p.Arg1138His) variant causes a missense change. The variant allele was found at a frequency of 0.000529 in 1,608,202 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000256.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -15 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
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MYBPC3 | ENST00000545968.6 | c.3413G>A | p.Arg1138His | missense_variant | Exon 31 of 35 | 5 | NM_000256.3 | ENSP00000442795.1 | ||
MYBPC3 | ENST00000399249.6 | c.3413G>A | p.Arg1138His | missense_variant | Exon 30 of 34 | 5 | ENSP00000382193.2 |
Frequencies
GnomAD3 genomes AF: 0.000993 AC: 151AN: 152134Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00113 AC: 267AN: 237226Hom.: 2 AF XY: 0.00109 AC XY: 140AN XY: 128786
GnomAD4 exome AF: 0.000481 AC: 700AN: 1455950Hom.: 4 Cov.: 35 AF XY: 0.000489 AC XY: 354AN XY: 723628
GnomAD4 genome AF: 0.000992 AC: 151AN: 152252Hom.: 0 Cov.: 32 AF XY: 0.00154 AC XY: 115AN XY: 74456
ClinVar
Submissions by phenotype
not provided Benign:4
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This variant is associated with the following publications: (PMID: 26332594, 22763267, 19150014, 21310275, 12110947, 22765922, 20800588, 29032884, 31006259) -
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Cardiomyopathy Benign:3
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Hypertrophic cardiomyopathy Uncertain:1Benign:1
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not specified Uncertain:1
proposed classification - variant undergoing re-assessment, contact laboratory -
Primary dilated cardiomyopathy Benign:1
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Hypertrophic cardiomyopathy 4 Benign:1
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Primary familial hypertrophic cardiomyopathy Benign:1
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Cardiovascular phenotype Benign:1
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. -
Hypertrophic cardiomyopathy 1 Benign:1
The MYBPC3 Arg1138His variant has been previously reported in both the Exome Aggregation Consortium dataset (http://exac.broadinstitute.org/) at a frequency of 0.017 (72 of 4168 in the European Finnish population), and at a frequency of 0.002 in the European sub-population of the 1000 genomes project (http://www.1000genomes.org/). We observed this variant in a single proband with typical HCM, presented 27 years and has no clear family history of disease. No other variants were identified. The variant has been reported in the literature (Jääskeläinen P, et al., 2002; García-Castro M, et al., 2009; Golbus JR, et al., 2012). Jääskeläinen et al. (2002) sequenced MYBPC3 in a Finnish HCM population and normal cohort, and identified this Arg1138His variant in multiple families (3 unrelated probands and 5 normal control samples). The variant does not co-segregate with disease and homozygous individuals did not express the HCM phenotype. Another report from Garcia-Castro et al. (2009) identified the Arg1138His variant in a single proband amongst a Spanish HCM population, however this proband is described as having no family history of disease and a concentric pattern of hypertrophy (IVS and PW 19mm). Arginine (Arg) at position 1138 is conserved across distantly related species, however the computational tool specifically designed to predict the effects of missense variants in HCM genes (Jordan DM, et al., 2011), cannot predict the outcome of this MYBPC3 Arg1138His variant. Due to the allele frequency of > 0.001 in population databases, and literature evidence, we classify this variant as "likely benign". -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at