10-68201918-G-A

Position:

chr10-68201918-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3BP4_ModerateBS1BS2

The ENST00000358913.10(MYPN):c.3583G>A(p.Val1195Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000199 in 1,614,172 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V1195V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00076 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 1 hom. )

Consequence

MYPN
ENST00000358913.10 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:3B:7O:1

Conservation

PhyloP100: 7.91

Variant links:

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]

MYPN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 10: AlphaMissense, BayesDel_noAF, Cadd, Dann, Eigen, M_CAP, MutationAssessor, phyloP100way_vertebrate, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.23150074).

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000762 (116/152288) while in subpopulation AFR AF= 0.00265 (110/41558). AF 95% confidence interval is 0.00225. There are 0 homozygotes in gnomad4. There are 56 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 116 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.3583G>A	p.Val1195Met	missense_variant	18/20	ENST00000358913.10	NP_115967.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYPN	ENST00000358913.10 linkuse as main transcript	c.3583G>A	p.Val1195Met	missense_variant	18/20	1	NM_032578.4	ENSP00000351790	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.000756

AC:

115

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00263

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000255

AC:

AN:

251060

Hom.:

AF XY:

0.000243

AC XY:

AN XY:

135698

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000751

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000141

AC:

206

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00287

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000101

Gnomad4 SAS exome

AF:

0.000603

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000762

AC:

116

AN:

152288

Hom.:

Cov.:

AF XY:

0.000752

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00265

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000168

Hom.:

Bravo

AF:

0.000752

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000255

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:3Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3Other:1

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 28, 2020	This variant is associated with the following publications: (PMID: 22892539, 22337857, 23299917, 18006477, 27896284) -
not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYPN)	Apr 27, 2012	- -

Dilated cardiomyopathy 1KK

Pathogenic:1Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 27, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2008	- -

not specified

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 17, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2017	The p.Val1195Met variant in MYPN has been reported in at least 2 individuals wit h DCM (Duboscq-Bidot 2008, LMM data). It has been reported in ClinVar (Variant I D: 31792) with conflicting interpretations. This variant has also been identifie d in 0.2% (53/24012) of African chromosomes by the Genome Aggregation Database ( gnomAD, http://gnomad.broadinstitute.org; dbSNP rs71534280). Computational predi ction tools and conservation analysis suggest that this variant may impact the p rotein, though this information is not predictive enough to determine pathogenic ity. A single in vitro functional study reports that the p.Val1195Met variant ma y impact protein function (Duboscq-Bidot 2008). However, these types of assays m ay not accurately represent biological function. In summary, the clinical signif icance of the p.Val1195Met variant is uncertain. -

MYPN-related myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 26, 2024

- -

MYPN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 10, 2019

This alteration is classified as likely 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

Pathogenic

0.82

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Pathogenic

0.32

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

.;.;.;T

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D;.;D

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Uncertain

0.44

MutationAssessor

Pathogenic

3.3

M;.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-2.5

D;N;N;.

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0010

D;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.75

MVP

0.85

MPC

0.61

ClinPred

0.14

GERP RS

5.2

Varity_R

0.42

gMVP

0.73

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over