rs7079481

Positions:

chr10-68199485-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000358913.10(MYPN):c.3403C>A(p.Pro1135Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,613,704 control chromosomes in the GnomAD database, including 179,304 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P1135P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.41 ( 13473 hom., cov: 31)

Exomes 𝑓: 0.47 ( 165831 hom. )

Consequence

MYPN
ENST00000358913.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13O: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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006650597).

BP6

Variant 10-68199485-C-A is Benign according to our data. Variant chr10-68199485-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 31800.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68199485-C-A is described in Lovd as [Benign]. Variant chr10-68199485-C-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.3403C>A	p.Pro1135Thr	missense_variant	17/20	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.3403C>A	p.Pro1135Thr	missense_variant	17/20	1	NM_032578.4	ENSP00000351790	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.406

AC:

61673

AN:

151844

Hom.:

13474

Cov.:

show subpopulations

Gnomad AFR

AF:

0.261

Gnomad AMI

AF:

0.421

Gnomad AMR

AF:

0.417

Gnomad ASJ

AF:

0.325

Gnomad EAS

AF:

0.236

Gnomad SAS

AF:

0.429

Gnomad FIN

AF:

0.527

Gnomad MID

AF:

0.248

Gnomad NFE

AF:

0.490

Gnomad OTH

AF:

0.392

GnomAD3 exomes

AF:

0.432

AC:

108580

AN:

251350

Hom.:

24653

AF XY:

0.437

AC XY:

59406

AN XY:

135838

show subpopulations

Gnomad AFR exome

AF:

0.255

Gnomad AMR exome

AF:

0.419

Gnomad ASJ exome

AF:

0.333

Gnomad EAS exome

AF:

0.218

Gnomad SAS exome

AF:

0.431

Gnomad FIN exome

AF:

0.527

Gnomad NFE exome

AF:

0.487

Gnomad OTH exome

AF:

0.426

GnomAD4 exome

AF:

0.472

AC:

689882

AN:

1461740

Hom.:

165831

Cov.:

AF XY:

0.472

AC XY:

343063

AN XY:

727180

show subpopulations

Gnomad4 AFR exome

AF:

0.255

Gnomad4 AMR exome

AF:

0.416

Gnomad4 ASJ exome

AF:

0.330

Gnomad4 EAS exome

AF:

0.266

Gnomad4 SAS exome

AF:

0.435

Gnomad4 FIN exome

AF:

0.524

Gnomad4 NFE exome

AF:

0.494

Gnomad4 OTH exome

AF:

0.436

GnomAD4 genome

AF:

0.406

AC:

61683

AN:

151964

Hom.:

13473

Cov.:

AF XY:

0.406

AC XY:

30164

AN XY:

74268

show subpopulations

Gnomad4 AFR

AF:

0.261

Gnomad4 AMR

AF:

0.416

Gnomad4 ASJ

AF:

0.325

Gnomad4 EAS

AF:

0.236

Gnomad4 SAS

AF:

0.429

Gnomad4 FIN

AF:

0.527

Gnomad4 NFE

AF:

0.490

Gnomad4 OTH

AF:

0.392

Alfa

AF:

0.457

Hom.:

41717

Bravo

AF:

0.386

TwinsUK

AF:

0.496

AC:

1839

ALSPAC

AF:

0.485

AC:

1869

ESP6500AA

AF:

0.264

AC:

1163

ESP6500EA

AF:

0.479

AC:

4116

ExAC

AF:

0.432

AC:

52489

Asia WGS

AF:

0.306

AC:

1064

AN:

3478

EpiCase

AF:

0.479

EpiControl

AF:

0.469

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Pro1135Thr in exon 18 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 48% (4116/8600) of European Americ an chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.e du/EVS/; dbSNP rs7079481). -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 04, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	May 13, 2016	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 13, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Dilated cardiomyopathy 1KK

Benign:3

Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 29, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided

Benign:1Other:1

not provided, no classification provided	curation	Leiden Muscular Dystrophy (MYPN)	Apr 27, 2012	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

MYPN-related myopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Sep 05, 2021

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2015

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

Uncertain

0.50

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

.;.;.;T

Eigen

Uncertain

0.67

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

D;D;.;D

MetaRNN

Benign

0.0067

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.97

L;.;L;.

MutationTaster

Benign

1.5e-9

P;P;P

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.6

D;D;D;.

REVEL

Uncertain

0.44

Sift

Uncertain

0.0090

D;D;D;.

Sift4G

Uncertain

0.0060

D;D;D;D

Polyphen

1.0

D;D;D;.

Vest4

0.56

MPC

0.65

ClinPred

0.017

GERP RS

5.4

Varity_R

0.52

gMVP

0.48

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