rs138313730

chr10-68199563-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:15 O:1
• 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]

ACMG classification

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, Likely_benign=4, Uncertain_significance=2}. 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. This position pass quality control queck.
• BS2: High AC in GnomAd 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: 189 AN: 145398 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.000824

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00769

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00535

Gnomad SAS AF: 0.00112

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000199

Gnomad OTH AF: 0.000505

GnomAD3 exomes AF: 0.00381 AC: 957 AN: 251238 Hom.: 12 AF XY: 0.00305 AC XY: 414 AN XY: 135776

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.0227

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00506

Gnomad SAS exome AF: 0.000686

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000167

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.000977 AC: 1428 AN: 1461794 Hom.: 17 Cov.: 41 AF XY: 0.000887 AC XY: 645 AN XY: 727208

Gnomad4 AFR exome AF: 0.000358

Gnomad4 AMR exome AF: 0.0196

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00527

Gnomad4 SAS exome AF: 0.000754

Gnomad4 FIN exome AF: 0.000318

Gnomad4 NFE exome AF: 0.000182

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.00130 AC: 189 AN: 145522 Hom.: 4 Cov.: 31 AF XY: 0.00120 AC XY: 85 AN XY: 70734

Gnomad4 AFR AF: 0.000822

Gnomad4 AMR AF: 0.00775

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00516

Gnomad4 SAS AF: 0.00112

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000199

Gnomad4 OTH AF: 0.000500

Alfa AF: 0.000750 Hom.: 3

Bravo AF: 0.00254

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00330 AC: 400

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:15 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:6 Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYPN)	Apr 27, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 07, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 11, 2020	- -
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) -
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). -
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 -

Dilated cardiomyopathy 1KK Uncertain:2 Benign:4

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	- -
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. -
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	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
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). -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.088	T
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;.;D
MetaRNN	Benign	0.0083	T;T;T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Benign	1.9	L;.;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.7	N;N;N;.
REVEL	Pathogenic	0.71
Sift	Benign	0.047	D;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;D;D;.
Vest4		0.64
MVP		0.86
MPC		0.64
ClinPred		0.038	T
GERP RS		5.4
Varity_R		0.41
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs138313730; hg19: chr10-69959320;