rs16944397

Positions:

• chr18-3084009-A-G

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.4358T>C​(p.Met1453Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00939 in 1,585,514 control chromosomes in the GnomAD database, including 1,051 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.047 (540 hom., cov: 30)
  • Exomes 𝑓: 0.0054 (511 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.609

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=8.7073445E-4).
• BP6: Variant 18-3084009-A-G is Benign according to our data. Variant chr18-3084009-A-G is described in ClinVar as [Benign]. Clinvar id is 226823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.4358T>C	p.Met1453Thr	missense_variant	32/38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.4358T>C	p.Met1453Thr	missense_variant	32/38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.4070T>C	p.Met1357Thr	missense_variant	31/37	1		ENSP00000261606.7
MYOM1	ENST00000581075.1	n.*4T>C		non_coding_transcript_exon_variant	5/8	5		ENSP00000462039.1
MYOM1	ENST00000581075.1	n.*4T>C		3_prime_UTR_variant	5/8	5		ENSP00000462039.1

Frequencies

GnomAD3 genomes AF: 0.0469 AC: 7131 AN: 152036 Hom.: 540 Cov.: 30

Gnomad AFR AF: 0.161

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0214

Gnomad ASJ AF: 0.00806

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0123 AC: 2534 AN: 206282 Hom.: 188 AF XY: 0.00927 AC XY: 1021 AN XY: 110118

Gnomad AFR exome AF: 0.168

Gnomad AMR exome AF: 0.00893

Gnomad ASJ exome AF: 0.00487

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000117

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000683

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.00540 AC: 7742 AN: 1433360 Hom.: 511 Cov.: 31 AF XY: 0.00471 AC XY: 3345 AN XY: 709914

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.0111

Gnomad4 ASJ exome AF: 0.00711

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000293

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000774

Gnomad4 OTH exome AF: 0.0121

GnomAD4 genome AF: 0.0470 AC: 7153 AN: 152154 Hom.: 540 Cov.: 30 AF XY: 0.0447 AC XY: 3321 AN XY: 74368

Gnomad4 AFR AF: 0.161

Gnomad4 AMR AF: 0.0213

Gnomad4 ASJ AF: 0.00806

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000764

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.00841 Hom.: 207

Bravo AF: 0.0546

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.151 AC: 560

ESP6500EA AF: 0.00134 AC: 11

ExAC AF: 0.0130 AC: 1564

Asia WGS AF: 0.00866 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Met1453Thr in exon 32 of MYOM1: This variant is not expected to have clinical si gnificance because it has been identified in 15.1% (560/3712) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs16944397). -

MYOM1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 26, 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 10, 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	0.30
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.58
DEOGEN2	Benign	0.019	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.21	T;T;T
MetaRNN	Benign	0.00087	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	N;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	1.8	N;.;N
REVEL	Benign	0.034
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.029
MPC		0.16
ClinPred		0.0023	T
GERP RS		2.3
Varity_R		0.069
gMVP		0.50

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

Other links and lift over

dbSNP: rs16944397; hg19: chr18-3084007;