rs2230165

chr18-3188875-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003803.4(MYOM1):c.644C>T(p.Thr215Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,612,858 control chromosomes in the GnomAD database, including 3,226 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T215T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.075 (535 hom., cov: 30)
  • Exomes 𝑓: 0.057 (2691 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0990

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001524508).
• BP6: Variant 18-3188875-G-A is Benign according to our data. Variant chr18-3188875-G-A is described in ClinVar as [Benign]. Clinvar id is 226832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.644C>T	p.Thr215Met	missense_variant	4/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.644C>T	p.Thr215Met	missense_variant	4/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.644C>T	p.Thr215Met	missense_variant	4/37	1		A2

Frequencies

GnomAD3 genomes AF: 0.0751 AC: 11357 AN: 151310 Hom.: 538 Cov.: 30

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.0950

Gnomad EAS AF: 0.000781

Gnomad SAS AF: 0.0668

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0545

Gnomad OTH AF: 0.0788

GnomAD3 exomes AF: 0.0533 AC: 13270 AN: 248848 Hom.: 489 AF XY: 0.0536 AC XY: 7231 AN XY: 134978

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0342

Gnomad ASJ exome AF: 0.0882

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0609

Gnomad FIN exome AF: 0.0298

Gnomad NFE exome AF: 0.0554

Gnomad OTH exome AF: 0.0530

GnomAD4 exome AF: 0.0567 AC: 82908 AN: 1461430 Hom.: 2691 Cov.: 32 AF XY: 0.0565 AC XY: 41104 AN XY: 727008

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.0360

Gnomad4 ASJ exome AF: 0.0898

Gnomad4 EAS exome AF: 0.000302

Gnomad4 SAS exome AF: 0.0626

Gnomad4 FIN exome AF: 0.0287

Gnomad4 NFE exome AF: 0.0568

Gnomad4 OTH exome AF: 0.0630

GnomAD4 genome AF: 0.0750 AC: 11354 AN: 151428 Hom.: 535 Cov.: 30 AF XY: 0.0739 AC XY: 5459 AN XY: 73918

Gnomad4 AFR AF: 0.135

Gnomad4 AMR AF: 0.0566

Gnomad4 ASJ AF: 0.0950

Gnomad4 EAS AF: 0.000783

Gnomad4 SAS AF: 0.0669

Gnomad4 FIN AF: 0.0301

Gnomad4 NFE AF: 0.0545

Gnomad4 OTH AF: 0.0780

Alfa AF: 0.0596 Hom.: 447

Bravo AF: 0.0799

TwinsUK AF: 0.0583 AC: 216

ALSPAC AF: 0.0532 AC: 205

ESP6500AA AF: 0.130 AC: 531

ESP6500EA AF: 0.0586 AC: 490

ExAC AF: 0.0566 AC: 6837

EpiCase AF: 0.0593

EpiControl AF: 0.0595

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Thr215Met in exon 4 of MYOM1: This variant is not expected to have clinical sign ificance because it has been identified in 13.0% (531/4076) of African American chromosomes from a broad population by the NHLBI Exome Sequencing Project (http: //evs.gs.washington.edu/EVS; dbSNP rs2230165). -

MYOM1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 27, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 28, 2019

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2012

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	Benign	0.28
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.64
Cadd	Benign	5.2
Dann	Uncertain	0.98
DEOGEN2	Benign	0.014	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.54	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.10	N;.;N
REVEL	Benign	0.015
Sift	Benign	0.13	T;.;T
Sift4G	Benign	0.30	T;T;T
Polyphen		0.90	P;.;B
Vest4		0.11
MPC		0.22
ClinPred		0.0025	T
Varity_R		0.041
gMVP		0.20

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

Other links and lift over

dbSNP: rs2230165; hg19: chr18-3188873; COSMIC: COSV55297516; COSMIC: COSV55297516;