18-3215160-C-G

Position:

chr18-3215160-C-G

Variant summary

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

The NM_003803.4(MYOM1):c.64G>C(p.Val22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0968 in 1,613,376 control chromosomes in the GnomAD database, including 7,946 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 847 hom., cov: 32)

Exomes 𝑓: 0.096 ( 7099 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 3.12

Variant links:

Genes affected

MYOM1 (HGNC:7613): (myomesin 1) The giant protein titin, together with its associated proteins, interconnects the major structure of sarcomeres, the M bands and Z discs. The C-terminal end of the titin string extends into the M line, where it binds tightly to M-band constituents of apparent molecular masses of 190 kD (myomesin 1) and 165 kD (myomesin 2). This protein, myomesin 1, like myomesin 2, titin, and other myofibrillar proteins contains structural modules with strong homology to either fibronectin type III (motif I) or immunoglobulin C2 (motif II) domains. Myomesin 1 and myomesin 2 each have a unique N-terminal region followed by 12 modules of motif I or motif II, in the arrangement II-II-I-I-I-I-I-II-II-II-II-II. The two proteins share 50% sequence identity in this repeat-containing region. The head structure formed by these 2 proteins on one end of the titin string extends into the center of the M band. The integrating structure of the sarcomere arises from muscle-specific members of the superfamily of immunoglobulin-like proteins. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

MYOM1 links:

MYOM1 (HGNC:):

MYOM1 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=0.0012019873).

BP6

Variant 18-3215160-C-G is Benign according to our data. Variant chr18-3215160-C-G is described in ClinVar as [Benign]. Clinvar id is 226833.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.168 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.64G>C	p.Val22Leu	missense_variant	2/38	ENST00000356443.9	NP_003794.3	P52179-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.64G>C	p.Val22Leu	missense_variant	2/38	1	NM_003803.4	ENSP00000348821.4	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.64G>C	p.Val22Leu	missense_variant	2/37	1		ENSP00000261606.7	P52179-2
ENSG00000265399	ENST00000580139.1 linkuse as main transcript	n.198-1832C>G		intron_variant		2

Frequencies

GnomAD3 genomes

AF:

0.103

AC:

15707

AN:

152074

Hom.:

849

Cov.:

show subpopulations

Gnomad AFR

AF:

0.123

Gnomad AMI

AF:

0.172

Gnomad AMR

AF:

0.0928

Gnomad ASJ

AF:

0.0816

Gnomad EAS

AF:

0.177

Gnomad SAS

AF:

0.119

Gnomad FIN

AF:

0.0924

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0898

Gnomad OTH

AF:

0.0846

GnomAD3 exomes

AF:

0.0990

AC:

24499

AN:

247380

Hom.:

1309

AF XY:

0.0989

AC XY:

13284

AN XY:

134384

show subpopulations

Gnomad AFR exome

AF:

0.119

Gnomad AMR exome

AF:

0.0722

Gnomad ASJ exome

AF:

0.0891

Gnomad EAS exome

AF:

0.169

Gnomad SAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0974

Gnomad NFE exome

AF:

0.0917

Gnomad OTH exome

AF:

0.0967

GnomAD4 exome

AF:

0.0961

AC:

140395

AN:

1461184

Hom.:

7099

Cov.:

AF XY:

0.0963

AC XY:

70015

AN XY:

726828

show subpopulations

Gnomad4 AFR exome

AF:

0.116

Gnomad4 AMR exome

AF:

0.0726

Gnomad4 ASJ exome

AF:

0.0932

Gnomad4 EAS exome

AF:

0.183

Gnomad4 SAS exome

AF:

0.111

Gnomad4 FIN exome

AF:

0.100

Gnomad4 NFE exome

AF:

0.0920

Gnomad4 OTH exome

AF:

0.102

GnomAD4 genome

AF:

0.103

AC:

15710

AN:

152192

Hom.:

847

Cov.:

AF XY:

0.104

AC XY:

7714

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.123

Gnomad4 AMR

AF:

0.0928

Gnomad4 ASJ

AF:

0.0816

Gnomad4 EAS

AF:

0.177

Gnomad4 SAS

AF:

0.119

Gnomad4 FIN

AF:

0.0924

Gnomad4 NFE

AF:

0.0898

Gnomad4 OTH

AF:

0.0823

Alfa

AF:

0.0833

Hom.:

379

Bravo

AF:

0.103

TwinsUK

AF:

0.0868

AC:

322

ALSPAC

AF:

0.0823

AC:

317

ESP6500AA

AF:

0.119

AC:

501

ESP6500EA

AF:

0.0859

AC:

729

ExAC

AF:

0.102

AC:

12319

EpiCase

AF:

0.0860

EpiControl

AF:

0.0857

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2018	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Val22Leu in exon 2 of MYOM1: This variant is not expected to have clinical signi ficance because it has been identified in 11.9% (501/4212) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS; dbSNP rs1791085). -

MYOM1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 21, 2013

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.42

T;T

MetaRNN

Benign

0.0012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

N;N

PrimateAI

Benign

0.40

PROVEAN

Benign

0.42

N;N

REVEL

Benign

0.086

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.054

MPC

0.14

ClinPred

0.0021

GERP RS

5.7

Varity_R

0.034

gMVP

0.35

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

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