rs79397275

chr18-3126890-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003803.4(MYOM1):c.2802A>G(p.Pro934=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,608,232 control chromosomes in the GnomAD database, including 86 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (15 hom., cov: 30)
  • Exomes 𝑓: 0.0020 (71 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.615

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 18-3126890-T-C is Benign according to our data. Variant chr18-3126890-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 416052.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.615 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0621 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.2802A>G	p.Pro934=	synonymous_variant	19/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.2802A>G	p.Pro934=	synonymous_variant	19/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.2514A>G	p.Pro838=	synonymous_variant	18/37	1		A2
MYOM1	ENST00000582016.1	n.358A>G		non_coding_transcript_exon_variant	2/3	4

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 451 AN: 152120 Hom.: 15 Cov.: 30

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0679

Gnomad SAS AF: 0.00269

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00545 AC: 1303 AN: 238952 Hom.: 35 AF XY: 0.00506 AC XY: 654 AN XY: 129162

Gnomad AFR exome AF: 0.000815

Gnomad AMR exome AF: 0.000513

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.0639

Gnomad SAS exome AF: 0.00311

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000537

Gnomad OTH exome AF: 0.00306

GnomAD4 exome AF: 0.00203 AC: 2954 AN: 1455994 Hom.: 71 Cov.: 31 AF XY: 0.00201 AC XY: 1453 AN XY: 723628

Gnomad4 AFR exome AF: 0.000479

Gnomad4 AMR exome AF: 0.000434

Gnomad4 ASJ exome AF: 0.000116

Gnomad4 EAS exome AF: 0.0489

Gnomad4 SAS exome AF: 0.00255

Gnomad4 FIN exome AF: 0.0000752

Gnomad4 NFE exome AF: 0.000393

Gnomad4 OTH exome AF: 0.00533

GnomAD4 genome AF: 0.00297 AC: 452 AN: 152238 Hom.: 15 Cov.: 30 AF XY: 0.00317 AC XY: 236 AN XY: 74426

Gnomad4 AFR AF: 0.000915

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0679

Gnomad4 SAS AF: 0.00270

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000250

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000716 Hom.: 0

Bravo AF: 0.00309

Asia WGS AF: 0.0310 AC: 107 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 24, 2014	Pro934Pro in exon 19 of MYOM1: This variant is not expected to have clinical sig nificance because it does not alter an amino acid residue and is not located wit hin the splice consensus sequence. It has been identified in 11.0% (22/200) of H an Chinese chromosomes from a broad population by the 1000 Genomes Project (http ://www.ncbi.nlm.nih.gov/projects/SNP; dbSNP rs79397275). -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2022	This alteration is classified as likely 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. -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	4.1
Dann	Benign	0.49

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: rs79397275; hg19: chr18-3126888;