rs7079481

chr10-68199485-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032578.4(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 NM_032578.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12 O:1
• Conservation: PhyloP100: 7.91

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 -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	UniProt
MYPN	NM_032578.4	c.3403C>A	p.Pro1135Thr	missense_variant	17/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.3403C>A	p.Pro1135Thr	missense_variant	17/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes AF: 0.406 AC: 61673 AN: 151844 Hom.: 13474 Cov.: 31

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

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.: 55 AF XY: 0.472 AC XY: 343063 AN XY: 727180

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.: 31 AF XY: 0.406 AC XY: 30164 AN XY: 74268

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:12 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

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	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	Clinical Genetics, Academic Medical Center	-	- -
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). -
Benign, criteria provided, single submitter	research	Biesecker Lab/Clinical Genomics Section, National Institutes of Health	Jun 24, 2013	- -
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	- -

Dilated cardiomyopathy 1KK Benign:3

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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	Invitae	Feb 01, 2024	- -

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. -

not provided Other:1

not provided, no classification provided

curation

Leiden Muscular Dystrophy (MYPN)

Apr 27, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Uncertain	0.67
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;.;D
MetaRNN	Benign	0.0067	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.97	L;.;L;.
MutationTaster	Benign	1.5e-9	P;P;P
PrimateAI	Uncertain	0.62	T
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	T
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

Other links and lift over

dbSNP: rs7079481; hg19: chr10-69959242; COSMIC: COSV62741889;