rs147659164

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_032578.4(MYPN):c.3846T>A(p.Ser1282Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000363 in 1,614,112 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00019 ( 1 hom. )

Consequence

MYPN
NM_032578.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 1.50

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:

LOC124902443 (HGNC:):

LOC124902443 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=0.00831148).

BP6

Variant 10-68210338-T-A is Benign according to our data. Variant chr10-68210338-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 192127.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-68210338-T-A is described in Lovd as [Benign]. Variant chr10-68210338-T-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00201 (306/152338) while in subpopulation AFR AF= 0.00707 (294/41568). AF 95% confidence interval is 0.00641. There are 0 homozygotes in gnomad4. There are 142 alleles in male gnomad4 subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd at 305 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYPN	NM_032578.4 linkuse as main transcript	c.3846T>A	p.Ser1282Arg	missense_variant	20/20	ENST00000358913.10
LOC124902443	XR_007062176.1 linkuse as main transcript	n.127+4950A>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYPN	ENST00000358913.10 linkuse as main transcript	c.3846T>A	p.Ser1282Arg	missense_variant	20/20	1	NM_032578.4	P1	Q86TC9-1

Frequencies

GnomAD3 genomes

AF:

0.00200

AC:

305

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00707

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000473

AC:

119

AN:

251428

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135884

show subpopulations

Gnomad AFR exome

AF:

0.00671

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000192

AC:

280

AN:

1461774

Hom.:

Cov.:

AF XY:

0.000168

AC XY:

122

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00708

Gnomad4 AMR exome

AF:

0.000313

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.00201

AC:

306

AN:

152338

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

142

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00707

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.000272

Hom.:

Bravo

AF:

0.00220

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000511

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 10, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 18, 2017	p.Ser1282Arg in exon 21 of MYPN: This variant is not expected to have clinical s ignificance because it has been identified in 0.7% (157/24030) of African chromo somes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.o rg/; dbSNP rs147659164). -

not provided

Benign:2

Likely 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	GeneDx	Nov 20, 2020	This variant is associated with the following publications: (PMID: 23861362) -

MYPN-related myopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Apr 04, 2024

- -

Dilated cardiomyopathy 1KK

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2018

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

0.84

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Uncertain

-0.080

Cadd

Benign

Dann

Uncertain

1.0

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.22

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D;.;D

M_CAP

Benign

0.044

MetaRNN

Benign

0.0083

T;T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Uncertain

2.0

M;.;M;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-2.6

D;D;D;.

REVEL

Uncertain

0.31

Sift

Uncertain

0.0010

D;D;D;.

Sift4G

Uncertain

0.0070

D;D;D;D

Polyphen

0.97

D;D;D;.

Vest4

0.37

MutPred

0.26

Gain of MoRF binding (P = 0.0149);.;Gain of MoRF binding (P = 0.0149);.;

MVP

0.72

MPC

0.48

ClinPred

0.058

GERP RS

1.2

Varity_R

0.57

gMVP

0.58

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