rs76382984

Positions:

chr18-3215133-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The ENST00000356443.9(MYOM1):c.91C>A(p.Arg31=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,613,742 control chromosomes in the GnomAD database, including 265 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. R31R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 25 hom., cov: 32)

Exomes 𝑓: 0.015 ( 240 hom. )

Consequence

MYOM1
ENST00000356443.9 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.56

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:

(HGNC:):

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=-0.49).

BP6

Variant 18-3215133-G-T is Benign according to our data. Variant chr18-3215133-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 226836.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3215133-G-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=3.56 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0126 (1912/152220) while in subpopulation EAS AF= 0.0416 (215/5166). AF 95% confidence interval is 0.0371. There are 25 homozygotes in gnomad4. There are 990 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.91C>A	p.Arg31=	synonymous_variant	2/38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.91C>A	p.Arg31=	synonymous_variant	2/38	1	NM_003803.4	ENSP00000348821	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.91C>A	p.Arg31=	synonymous_variant	2/37	1		ENSP00000261606	A2	P52179-2
	ENST00000580139.1 linkuse as main transcript	n.198-1859G>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.0126

AC:

1911

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00205

Gnomad AMI

AF:

0.0274

Gnomad AMR

AF:

0.00916

Gnomad ASJ

AF:

0.0204

Gnomad EAS

AF:

0.0413

Gnomad SAS

AF:

0.00560

Gnomad FIN

AF:

0.0333

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0143

Gnomad OTH

AF:

0.0101

GnomAD3 exomes

AF:

0.0172

AC:

4281

AN:

248290

Hom.:

AF XY:

0.0166

AC XY:

2235

AN XY:

134906

show subpopulations

Gnomad AFR exome

AF:

0.00202

Gnomad AMR exome

AF:

0.0131

Gnomad ASJ exome

AF:

0.0218

Gnomad EAS exome

AF:

0.0409

Gnomad SAS exome

AF:

0.00619

Gnomad FIN exome

AF:

0.0382

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.0171

GnomAD4 exome

AF:

0.0152

AC:

22255

AN:

1461522

Hom.:

240

Cov.:

AF XY:

0.0150

AC XY:

10894

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.00170

Gnomad4 AMR exome

AF:

0.0132

Gnomad4 ASJ exome

AF:

0.0219

Gnomad4 EAS exome

AF:

0.0352

Gnomad4 SAS exome

AF:

0.00637

Gnomad4 FIN exome

AF:

0.0398

Gnomad4 NFE exome

AF:

0.0145

Gnomad4 OTH exome

AF:

0.0142

GnomAD4 genome

AF:

0.0126

AC:

1912

AN:

152220

Hom.:

Cov.:

AF XY:

0.0133

AC XY:

990

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00205

Gnomad4 AMR

AF:

0.00915

Gnomad4 ASJ

AF:

0.0204

Gnomad4 EAS

AF:

0.0416

Gnomad4 SAS

AF:

0.00581

Gnomad4 FIN

AF:

0.0333

Gnomad4 NFE

AF:

0.0143

Gnomad4 OTH

AF:

0.00950

Alfa

AF:

0.0136

Hom.:

Bravo

AF:

0.0107

Asia WGS

AF:

0.0210

AC:

AN:

3478

EpiCase

AF:

0.0133

EpiControl

AF:

0.0129

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

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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Arg31Arg in exon 2 of MYOM1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 1.3% (108/8472) of Eu ropean American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs76382984). -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 10, 2019	- -
Likely 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

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.65

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