rs2230163

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003803.4(MYOM1):c.1146C>T(p.His382=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 1,609,322 control chromosomes in the GnomAD database, including 82,103 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 8693 hom., cov: 31)

Exomes 𝑓: 0.31 ( 73410 hom. )

Consequence

MYOM1
NM_003803.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.830

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 18-3173966-G-A is Benign according to our data. Variant chr18-3173966-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226798.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.83 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.402 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.1146C>T	p.His382=	synonymous_variant	8/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.1146C>T	p.His382=	synonymous_variant	8/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.1146C>T	p.His382=	synonymous_variant	8/37	1		A2	P52179-2

Frequencies

GnomAD3 genomes

AF:

0.334

AC:

50621

AN:

151654

Hom.:

8667

Cov.:

show subpopulations

Gnomad AFR

AF:

0.407

Gnomad AMI

AF:

0.265

Gnomad AMR

AF:

0.281

Gnomad ASJ

AF:

0.324

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.305

Gnomad FIN

AF:

0.296

Gnomad MID

AF:

0.253

Gnomad NFE

AF:

0.316

Gnomad OTH

AF:

0.337

GnomAD3 exomes

AF:

0.297

AC:

73857

AN:

248884

Hom.:

11286

AF XY:

0.298

AC XY:

40190

AN XY:

135024

show subpopulations

Gnomad AFR exome

AF:

0.410

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.315

Gnomad EAS exome

AF:

0.248

Gnomad SAS exome

AF:

0.305

Gnomad FIN exome

AF:

0.291

Gnomad NFE exome

AF:

0.312

Gnomad OTH exome

AF:

0.302

GnomAD4 exome

AF:

0.315

AC:

458672

AN:

1457550

Hom.:

73410

Cov.:

AF XY:

0.314

AC XY:

227692

AN XY:

725238

show subpopulations

Gnomad4 AFR exome

AF:

0.411

Gnomad4 AMR exome

AF:

0.217

Gnomad4 ASJ exome

AF:

0.319

Gnomad4 EAS exome

AF:

0.307

Gnomad4 SAS exome

AF:

0.304

Gnomad4 FIN exome

AF:

0.297

Gnomad4 NFE exome

AF:

0.318

Gnomad4 OTH exome

AF:

0.313

GnomAD4 genome

AF:

0.334

AC:

50698

AN:

151772

Hom.:

8693

Cov.:

AF XY:

0.330

AC XY:

24524

AN XY:

74206

show subpopulations

Gnomad4 AFR

AF:

0.408

Gnomad4 AMR

AF:

0.281

Gnomad4 ASJ

AF:

0.324

Gnomad4 EAS

AF:

0.266

Gnomad4 SAS

AF:

0.305

Gnomad4 FIN

AF:

0.296

Gnomad4 NFE

AF:

0.316

Gnomad4 OTH

AF:

0.339

Alfa

AF:

0.315

Hom.:

11258

Bravo

AF:

0.334

Asia WGS

AF:

0.293

AC:

1017

AN:

3478

EpiCase

AF:

0.314

EpiControl

AF:

0.304

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	His382His in exon 8 of MYOM1: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 39.2% (1462/3730) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs2230163). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2022	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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	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, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

5.6

DANN

Benign

0.48

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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