rs149528866

Positions:

• chr18-3135646-C-T

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.2110G>A​(p.Glu704Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00602 in 1,613,888 control chromosomes in the GnomAD database, including 71 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. E704E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (13 hom., cov: 31)
  • Exomes 𝑓: 0.0060 (58 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 7.91

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=0.011583).
• BP6: Variant 18-3135646-C-T is Benign according to our data. Variant chr18-3135646-C-T is described in ClinVar as [Benign]. Clinvar id is 226809.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3135646-C-T is described in Lovd as [Likely_pathogenic]. Variant chr18-3135646-C-T is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.2110G>A	p.Glu704Lys	missense_variant	15/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.2110G>A	p.Glu704Lys	missense_variant	15/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.2110G>A	p.Glu704Lys	missense_variant	15/37	1		A2
MYOM1	ENST00000577294.1	n.166G>A		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes AF: 0.00640 AC: 974 AN: 152094 Hom.: 13 Cov.: 31

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0353

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00644

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00638 AC: 1589 AN: 249158 Hom.: 11 AF XY: 0.00621 AC XY: 839 AN XY: 135188

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.00139

Gnomad ASJ exome AF: 0.0166

Gnomad EAS exome AF: 0.00184

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0329

Gnomad NFE exome AF: 0.00512

Gnomad OTH exome AF: 0.00678

GnomAD4 exome AF: 0.00598 AC: 8736 AN: 1461676 Hom.: 58 Cov.: 30 AF XY: 0.00586 AC XY: 4263 AN XY: 727122

Gnomad4 AFR exome AF: 0.000717

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.0161

Gnomad4 EAS exome AF: 0.000680

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0341

Gnomad4 NFE exome AF: 0.00531

Gnomad4 OTH exome AF: 0.00729

GnomAD4 genome AF: 0.00640 AC: 974 AN: 152212 Hom.: 13 Cov.: 31 AF XY: 0.00735 AC XY: 547 AN XY: 74420

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.00321

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00135

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0353

Gnomad4 NFE AF: 0.00644

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00562 Hom.: 5

Bravo AF: 0.00371

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000257 AC: 1

ESP6500EA AF: 0.00387 AC: 32

ExAC AF: 0.00576 AC: 696

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00540

EpiControl AF: 0.00362

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

Glu704Lys in exon 15 of MYOM1: This variant is not expected to have clinical sig nificance because it has been identified in 3.2% (6/186) of Finnish chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov /projects/SNP; dbSNP rs149528866). -

MYOM1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 25, 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 29, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 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	Uncertain	0.40
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.065	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D;D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.84	L;.;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.3	N;.;N
REVEL	Uncertain	0.38
Sift	Benign	0.057	T;.;T
Sift4G	Benign	0.21	T;T;T
Polyphen		1.0	D;.;D
Vest4		0.89
MVP		0.89
MPC		0.66
ClinPred		0.055	T
GERP RS		6.0
Varity_R		0.38
gMVP		0.71

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

Other links and lift over

dbSNP: rs149528866; hg19: chr18-3135644;