rs9964300

chr18-3215032-C-Achr18-3215032-C-T

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.192G>T(p.Ala64=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0625 in 1,612,418 control chromosomes in the GnomAD database, including 3,559 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.082 (621 hom., cov: 32)
  • Exomes 𝑓: 0.060 (2938 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.711

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 18-3215032-C-A is Benign according to our data. Variant chr18-3215032-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 226808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.711 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.192G>T	p.Ala64=	synonymous_variant	2/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.192G>T	p.Ala64=	synonymous_variant	2/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.192G>T	p.Ala64=	synonymous_variant	2/37	1		A2
	ENST00000580139.1	n.198-1960C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0821 AC: 12485 AN: 152136 Hom.: 616 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.0395

Gnomad AMR AF: 0.0972

Gnomad ASJ AF: 0.0236

Gnomad EAS AF: 0.00695

Gnomad SAS AF: 0.0480

Gnomad FIN AF: 0.0605

Gnomad MID AF: 0.0605

Gnomad NFE AF: 0.0626

Gnomad OTH AF: 0.0732

GnomAD3 exomes AF: 0.0631 AC: 15468 AN: 245234 Hom.: 598 AF XY: 0.0606 AC XY: 8085 AN XY: 133446

Gnomad AFR exome AF: 0.133

Gnomad AMR exome AF: 0.0848

Gnomad ASJ exome AF: 0.0241

Gnomad EAS exome AF: 0.00684

Gnomad SAS exome AF: 0.0493

Gnomad FIN exome AF: 0.0606

Gnomad NFE exome AF: 0.0640

Gnomad OTH exome AF: 0.0549

GnomAD4 exome AF: 0.0604 AC: 88202 AN: 1460164 Hom.: 2938 Cov.: 33 AF XY: 0.0598 AC XY: 43400 AN XY: 726252

Gnomad4 AFR exome AF: 0.135

Gnomad4 AMR exome AF: 0.0863

Gnomad4 ASJ exome AF: 0.0245

Gnomad4 EAS exome AF: 0.00766

Gnomad4 SAS exome AF: 0.0510

Gnomad4 FIN exome AF: 0.0611

Gnomad4 NFE exome AF: 0.0608

Gnomad4 OTH exome AF: 0.0578

GnomAD4 genome AF: 0.0823 AC: 12523 AN: 152254 Hom.: 621 Cov.: 32 AF XY: 0.0809 AC XY: 6025 AN XY: 74442

Gnomad4 AFR AF: 0.134

Gnomad4 AMR AF: 0.0972

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.00696

Gnomad4 SAS AF: 0.0481

Gnomad4 FIN AF: 0.0605

Gnomad4 NFE AF: 0.0626

Gnomad4 OTH AF: 0.0724

Alfa AF: 0.0527 Hom.: 139

Bravo AF: 0.0841

Asia WGS AF: 0.0460 AC: 160 AN: 3478

EpiCase AF: 0.0557

EpiControl AF: 0.0579

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

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	Ala64Ala in exon 2 of MYOM1: This variant is not expected to have clinical signi ficance because it does not alter an amino acid residue and is not located withi n the splice consensus sequence. It has been identified in 11.6% (473/4072) of A frican American chromosomes from a broad population by the NHLBI Exome Sequencin g Project (http://evs.gs.washington.edu/EVS; dbSNP rs9964300). -
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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 06, 2019

- -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	0.15
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs9964300; hg19: chr18-3215030;