rs1071600

Positions:

• chr18-3126813-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.2879T>C​(p.Ile960Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,612,564 control chromosomes in the GnomAD database, including 23,059 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3268 hom., cov: 30)
  • Exomes 𝑓: 0.15 (19791 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.467

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=0.0035020113).
• BP6: Variant 18-3126813-A-G is Benign according to our data. Variant chr18-3126813-A-G is described in ClinVar as [Benign]. Clinvar id is 226815.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.2879T>C	p.Ile960Thr	missense_variant	19/38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.2879T>C	p.Ile960Thr	missense_variant	19/38	1	NM_003803.4	ENSP00000348821	P2
MYOM1	ENST00000261606.11	c.2591T>C	p.Ile864Thr	missense_variant	18/37	1		ENSP00000261606	A2
MYOM1	ENST00000582016.1	n.435T>C		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29647 AN: 151878 Hom.: 3249 Cov.: 30

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.234

Gnomad AMR AF: 0.210

Gnomad ASJ AF: 0.165

Gnomad EAS AF: 0.328

Gnomad SAS AF: 0.247

Gnomad FIN AF: 0.188

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.203

GnomAD3 exomes AF: 0.193 AC: 47845 AN: 247648 Hom.: 5063 AF XY: 0.193 AC XY: 25948 AN XY: 134352

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.232

Gnomad ASJ exome AF: 0.156

Gnomad EAS exome AF: 0.320

Gnomad SAS exome AF: 0.243

Gnomad FIN exome AF: 0.184

Gnomad NFE exome AF: 0.143

Gnomad OTH exome AF: 0.184

GnomAD4 exome AF: 0.155 AC: 225949 AN: 1460568 Hom.: 19791 Cov.: 32 AF XY: 0.158 AC XY: 114469 AN XY: 726498

Gnomad4 AFR exome AF: 0.280

Gnomad4 AMR exome AF: 0.227

Gnomad4 ASJ exome AF: 0.158

Gnomad4 EAS exome AF: 0.322

Gnomad4 SAS exome AF: 0.245

Gnomad4 FIN exome AF: 0.174

Gnomad4 NFE exome AF: 0.133

Gnomad4 OTH exome AF: 0.175

GnomAD4 genome AF: 0.196 AC: 29716 AN: 151996 Hom.: 3268 Cov.: 30 AF XY: 0.200 AC XY: 14879 AN XY: 74290

Gnomad4 AFR AF: 0.265

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.165

Gnomad4 EAS AF: 0.328

Gnomad4 SAS AF: 0.246

Gnomad4 FIN AF: 0.188

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.211

Alfa AF: 0.158 Hom.: 4339

Bravo AF: 0.200

TwinsUK AF: 0.135 AC: 502

ALSPAC AF: 0.129 AC: 498

ESP6500AA AF: 0.261 AC: 1017

ESP6500EA AF: 0.142 AC: 1175

ExAC AF: 0.193 AC: 23291

Asia WGS AF: 0.318 AC: 1105 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2019	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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Ile960Thr in exon 19 of MYOM1: This variant is not expected to have clinical sig nificance because it has been identified in 26.1% (1017/3904) of African America n chromosomes from a broad population by the NHLBI Exome Sequencing Project (htt p://evs.gs.washington.edu/EVS; dbSNP rs1071600). -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	5.6
DANN	Benign	0.60
DEOGEN2	Benign	0.023	T;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.099	N
LIST_S2	Benign	0.79	T;T;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.34	N;.;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.30	T
PROVEAN	Benign	1.6	N;.;N
REVEL	Benign	0.052
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.034
MPC		0.18
ClinPred		0.00030	T
GERP RS		1.4
Varity_R		0.066
gMVP		0.43

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: rs1071600; hg19: chr18-3126811; COSMIC: COSV55287620;