18-3071880-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003803.4(MYOM1):c.4718G>A(p.Arg1573Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,604,694 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1573W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0032 (7 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (52 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 7.66

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=0.009976715).
• BP6: Variant 18-3071880-C-T is Benign according to our data. Variant chr18-3071880-C-T is described in ClinVar as [Benign]. Clinvar id is 226827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3071880-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00319 (485/152266) while in subpopulation AMR AF= 0.0232 (354/15290). AF 95% confidence interval is 0.0212. There are 7 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.4718G>A	p.Arg1573Gln	missense_variant	37/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.4718G>A	p.Arg1573Gln	missense_variant	37/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.4430G>A	p.Arg1477Gln	missense_variant	36/37	1		A2
MYOM1	ENST00000581804.1	n.208G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.00317 AC: 482 AN: 152148 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0230

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0143

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00758 AC: 1771 AN: 233670 Hom.: 41 AF XY: 0.00578 AC XY: 729 AN XY: 126142

Gnomad AFR exome AF: 0.000785

Gnomad AMR exome AF: 0.0430

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0168

Gnomad SAS exome AF: 0.000429

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00452

GnomAD4 exome AF: 0.00181 AC: 2624 AN: 1452428 Hom.: 52 Cov.: 30 AF XY: 0.00155 AC XY: 1116 AN XY: 721354

Gnomad4 AFR exome AF: 0.000601

Gnomad4 AMR exome AF: 0.0417

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0148

Gnomad4 SAS exome AF: 0.000298

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000488

Gnomad4 OTH exome AF: 0.00201

GnomAD4 genome AF: 0.00319 AC: 485 AN: 152266 Hom.: 7 Cov.: 32 AF XY: 0.00325 AC XY: 242 AN XY: 74438

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.0232

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00116 Hom.: 4

Bravo AF: 0.00563

ESP6500AA AF: 0.000498 AC: 2

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.00519 AC: 628

Asia WGS AF: 0.00693 AC: 24 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

Arg1573Gln in exon 37 of MYOM1: This variant is not expected to have clinical si gnificance because it has been identified in 4.5% (6/132) of Mexican chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.go v/projects/SNP; dbSNP rs117342470). -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 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	Benign	0.24
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Pathogenic	27
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.25	T;.;.
Eigen	Pathogenic	0.72
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D
MetaRNN	Benign	0.010	T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Uncertain	2.4	M;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.9	D;.;D
REVEL	Uncertain	0.31
Sift	Uncertain	0.0050	D;.;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.88
MVP		0.80
MPC		0.67
ClinPred		0.023	T
GERP RS		4.9
Varity_R		0.71
gMVP		0.65

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: rs117342470; hg19: chr18-3071878; COSMIC: COSV55303850; COSMIC: COSV55303850;