rs188677538

chr18-3135694-T-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003803.4(MYOM1):c.2062A>T(p.Thr688Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00354 in 1,613,898 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T688M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0036 (23 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 6.21

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010278076).
• BP6: Variant 18-3135694-T-A is Benign according to our data. Variant chr18-3135694-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 227694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3135694-T-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.2062A>T	p.Thr688Ser	missense_variant	15/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.2062A>T	p.Thr688Ser	missense_variant	15/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.2062A>T	p.Thr688Ser	missense_variant	15/37	1		A2
MYOM1	ENST00000577294.1	n.118A>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00264 AC: 402 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00962

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00354

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00298 AC: 742 AN: 249122 Hom.: 6 AF XY: 0.00287 AC XY: 388 AN XY: 135170

Gnomad AFR exome AF: 0.000323

Gnomad AMR exome AF: 0.000377

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0127

Gnomad NFE exome AF: 0.00382

Gnomad OTH exome AF: 0.00298

GnomAD4 exome AF: 0.00364 AC: 5318 AN: 1461672 Hom.: 23 Cov.: 30 AF XY: 0.00359 AC XY: 2608 AN XY: 727118

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.00404

Gnomad4 OTH exome AF: 0.00253

GnomAD4 genome AF: 0.00264 AC: 402 AN: 152226 Hom.: 0 Cov.: 31 AF XY: 0.00265 AC XY: 197 AN XY: 74430

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00962

Gnomad4 NFE AF: 0.00354

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.00305 Hom.: 1

Bravo AF: 0.00179

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000511 AC: 2

ESP6500EA AF: 0.00241 AC: 20

ExAC AF: 0.00270 AC: 327

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00243

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Thr688Ser in exon 15 of MYOM1: This variant is not expected to have clinical sig nificance because it has been identified in 2.7% (5/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs188677538). -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 22, 2018	This alteration is classified as 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. -

MYOM1-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 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

Invitae

Jan 26, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
Cadd	Uncertain	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.045	T;.;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T;T;T
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	0.99	D;D;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.8	N;.;N
REVEL	Benign	0.16
Sift	Uncertain	0.0050	D;.;T
Sift4G	Benign	0.26	T;T;T
Polyphen		0.93	P;.;P
Vest4		0.63
MVP		0.82
MPC		0.49
ClinPred		0.017	T
GERP RS		5.8
Varity_R		0.33
gMVP		0.32

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: rs188677538; hg19: chr18-3135692;