rs138313730
Positions:
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
Genomes: 𝑓 0.0013 ( 4 hom., cov: 31)
Exomes 𝑓: 0.00098 ( 17 hom. )
Consequence
MYPN
NM_032578.4 missense
NM_032578.4 missense
Scores
5
5
7
Clinical Significance
Conservation
PhyloP100: 5.03
Genes affected
MYPN (HGNC:23246): (myopalladin) Striated muscle in vertebrates comprises large proteins which must be organized properly to contract efficiently. Z-lines in striated muscle are a sign of this organization, representing the ends of actin thin filaments, titin, nebulin or nebulette and accessory proteins required for structure and function. This gene encodes a protein which interacts with nebulin in skeletal muscle or nebulette in cardiac muscle and alpha-actinin. In addition, this gene product can interact with a protein with the I-band indicating it has a regulatory as well as structural function. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2011]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -13 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.008320689).
BP6
?
Variant 10-68199563-C-A is Benign according to our data. Variant chr10-68199563-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 31819.We mark this variant Likely_benign, oryginal submissions are: {Benign=8, not_provided=1, Uncertain_significance=2, Likely_benign=4}. Variant chr10-68199563-C-A is described in Lovd as [Likely_benign]. Variant chr10-68199563-C-A is described in Lovd as [Benign]. Variant chr10-68199563-C-A is described in Lovd as [Likely_pathogenic].
BS1
?
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0013 (189/145522) while in subpopulation AMR AF= 0.00775 (111/14322). AF 95% confidence interval is 0.00658. There are 4 homozygotes in gnomad4. There are 85 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 189 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYPN | NM_032578.4 | c.3481C>A | p.Leu1161Ile | missense_variant | 17/20 | ENST00000358913.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYPN | ENST00000358913.10 | c.3481C>A | p.Leu1161Ile | missense_variant | 17/20 | 1 | NM_032578.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00130 AC: 189AN: 145398Hom.: 4 Cov.: 31
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GnomAD3 exomes AF: 0.00381 AC: 957AN: 251238Hom.: 12 AF XY: 0.00305 AC XY: 414AN XY: 135776
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GnomAD4 exome AF: 0.000977 AC: 1428AN: 1461794Hom.: 17 Cov.: 41 AF XY: 0.000887 AC XY: 645AN XY: 727208
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GnomAD4 genome ? AF: 0.00130 AC: 189AN: 145522Hom.: 4 Cov.: 31 AF XY: 0.00120 AC XY: 85AN XY: 70734
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:15Other:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:6Other:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 03, 2021 | 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) - |
not provided, no classification provided | curation | Leiden Muscular Dystrophy (MYPN) | Apr 27, 2012 | - - |
Likely benign, no assertion criteria provided | clinical testing | Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Oct 01, 2023 | MYPN: BS1, BS2 - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Aug 11, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Feb 07, 2017 | - - |
Benign, no assertion criteria provided | provider interpretation | Stanford Center for Inherited Cardiovascular Disease, Stanford University | Oct 13, 2016 | 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). - |
Dilated cardiomyopathy 1KK Uncertain:2Benign:4
Uncertain significance, criteria provided, single submitter | reference population | Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center | Mar 18, 2016 | - - |
Benign, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | - | 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. - |
Uncertain significance, no assertion criteria provided | literature only | ClinVar Staff, National Center for Biotechnology Information (NCBI) | Jun 27, 2013 | - - |
Benign, criteria provided, single submitter | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | May 31, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | Jul 28, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
not specified Benign:3
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Jun 03, 2015 | 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). - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 29, 2023 | - - |
Primary familial dilated cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute | Mar 28, 2017 | - - |
Primary dilated cardiomyopathy;C0018801:Heart failure;C0878544: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 | Jan 24, 2019 | - - |
Cardiovascular phenotype Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 25, 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;.;D
MetaRNN
Benign
T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;L;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N;N;.
REVEL
Pathogenic
Sift
Benign
D;D;D;.
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;D;D;.
Vest4
MVP
MPC
0.64
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at