rs138313730
Variant summary
Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2
The NM_032578.4(MYPN):c.3481C>A(p.Leu1161Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,607,316 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_032578.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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MYPN | NM_032578.4 | c.3481C>A | p.Leu1161Ile | missense_variant | Exon 17 of 20 | ENST00000358913.10 | NP_115967.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.00130 AC: 189AN: 145398Hom.: 4 Cov.: 31
GnomAD3 exomes AF: 0.00381 AC: 957AN: 251238Hom.: 12 AF XY: 0.00305 AC XY: 414AN XY: 135776
GnomAD4 exome AF: 0.000977 AC: 1428AN: 1461794Hom.: 17 Cov.: 41 AF XY: 0.000887 AC XY: 645AN XY: 727208
GnomAD4 genome AF: 0.00130 AC: 189AN: 145522Hom.: 4 Cov.: 31 AF XY: 0.00120 AC XY: 85AN XY: 70734
ClinVar
Submissions by phenotype
not provided Benign:6Other:1
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Identified in a patient with HCM in the published literature (Purevjav et al., 2012); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23299917, 22286171, 27535533) -
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p.Leu1161Ile (c.3481 C>A) in the MYPN gene Given the weak disease-gene association, the weak case data, and the presence in ancestry-matched general population samples, we consider this variant a variant of uncertain significance. MYPN (NM_032578.2) encodes myopalladin, a protein component of the sarcomere. Heterozygous mutations in MYPN have been reported in hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM) and restrictive cardiomyopathy (RCM) (Purevjav et al. 2012 Hum Molec Genet 21(9):2039-2053; Meyer et al. 2012 Eur J Hum Genet Epub ahead of print). However, when Megan Grove from our team reviewed the supporting data in 2012 we felt that it was weak. The variant has been seen in at least 1 unrelated case of hypertrophic cardiomyopathy (not including this patient's family). There is no segregation data available. Purevjav et al (2012) observed the variant in an American Indian/Alaskan male with HCM who had undergone myectomy. In silico analysis with PolyPhen-2 predicts the variant to be damaging. The variant occurs in the alpha-actinin binding domain. This is a conservative amino acid change from nonpolar leucine to a nonpolar isoleucine at a residue that is highly conserved across vertebrate species (it is a nonpolar phenylalanine in squirrel). It is predicted to be "probably damaging" and "tolerated" by PolyPhen and SIFT in silico analyses, respectively. [UPDATED in 2016] In total the variant has not been seen in at least 400 of >60,000 published controls and individuals from publicly available population datasets. It is present in 400 individuals in ExAC, across multiple ethnicities. The variant was reported in 3 of 4300 Caucasian individuals and 0 of 2203 African-American individuals in the NHLBI Exome Sequencing Project dataset (as of September 12th, 2014). The phenotype of those individuals is not publicly available. The dataset is comprised of multiple cohorts, some of which were recruited from the general population, others were enriched for common cardiovascular disease. Note that other variants with strong evidence for pathogenicity have been seen at similar frequencies in this dataset so this does not necessarily rule out pathogenicity (Pan et al 2012). Per GeneDx, the variant was observed in the 1000 Genomes samples: 3/551 (0.5%) alleles from individuals of Asian background and in 1/349 (0.3%) alleles of individuals of Hispanic ancestry. The variant was not observed in the following published control samples: 1020 (Purejeav et al 2012). -
MYPN: BS1, BS2 -
Dilated cardiomyopathy 1KK Uncertain:2Benign:4
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The heterozygous p.Leu1161Ile variant in MYPN has been identified in an American Indian Alaskan individual with hypertrophic cardiomyopathy (PMID: 22286171). This variant has also been identified in >2% of Latino chromosomes and 5 homozygotes by ExAC (http://gnomad.broadinstitute.org/), and in 3 individuals from the NHLBI GO Exome Sequencing Project (PMID: 23299917). In summary, this variant meets criteria to be classified as benign for hypertrophic cardiomyopathy. -
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not specified Benign:3
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p.Leu1161Ile in exon 18 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 2.8% (320/11566) of Latino chromos omes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs138313730). -
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Primary familial dilated cardiomyopathy Uncertain:1
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Primary dilated cardiomyopathy;C0018801:Heart failure;C0878544: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. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at