rs74143022

chr10-68122281-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032578.4(MYPN):c.843A>G(p.Pro281=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00644 in 1,613,930 control chromosomes in the GnomAD database, including 519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (271 hom., cov: 32)
  • Exomes 𝑓: 0.0037 (248 hom.)
• Consequence: MYPN NM_032578.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: -0.543

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 10-68122281-A-G is Benign according to our data. Variant chr10-68122281-A-G is described in ClinVar as [Benign]. Clinvar id is 31826.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68122281-A-G is described in Lovd as [Benign]. Variant chr10-68122281-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.543 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4	c.843A>G	p.Pro281=	synonymous_variant	2/20	ENST00000358913.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10	c.843A>G	p.Pro281=	synonymous_variant	2/20	1	NM_032578.4	P1

Frequencies

GnomAD3 genomes AF: 0.0327 AC: 4982 AN: 152178 Hom.: 270 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0142

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000603

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.00883 AC: 2207 AN: 249860 Hom.: 112 AF XY: 0.00672 AC XY: 910 AN XY: 135348

Gnomad AFR exome AF: 0.116

Gnomad AMR exome AF: 0.00796

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.000786

Gnomad NFE exome AF: 0.000469

Gnomad OTH exome AF: 0.00625

GnomAD4 exome AF: 0.00369 AC: 5398 AN: 1461634 Hom.: 248 Cov.: 31 AF XY: 0.00326 AC XY: 2371 AN XY: 727096

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.00828

Gnomad4 ASJ exome AF: 0.000230

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.000431

Gnomad4 NFE exome AF: 0.000457

Gnomad4 OTH exome AF: 0.00826

GnomAD4 genome AF: 0.0328 AC: 5002 AN: 152296 Hom.: 271 Cov.: 32 AF XY: 0.0323 AC XY: 2409 AN XY: 74492

Gnomad4 AFR AF: 0.113

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0158 Hom.: 67

Bravo AF: 0.0391

Asia WGS AF: 0.00779 AC: 27 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

Significance: Benign

Submissions summary: Benign:8 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 13, 2015	p.Pro281Pro in exon 3 of MYPN: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 10.3% (453/4406) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs74143022). -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 24, 2014	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. -

Dilated cardiomyopathy 1KK Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 08, 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. -

Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 20, 2021

- -

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
BayesDel_noAF	Benign	-0.64
Cadd	Benign	7.9
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs74143022; hg19: chr10-69882038;