chr18-3215032-C-A

Variant names:

• chr18-3215032-C-A
• rs9964300
• NM_003803.4:c.192G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003803.4(MYOM1):​c.192G>T​(p.Ala64Ala) 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:5
• Conservation: PhyloP100: -0.711
• Publications: 6 publications found

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]

MYOM1 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ENSG00000265399 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003803.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.192G>T	p.Ala64Ala	synonymous	Exon 2 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.192G>T	p.Ala64Ala	synonymous	Exon 2 of 37	NP_062830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	ENST00000356443.9	TSL:1 MANE Select	c.192G>T	p.Ala64Ala	synonymous	Exon 2 of 38	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.192G>T	p.Ala64Ala	synonymous	Exon 2 of 37	ENSP00000261606.7
	ENSG00000265399	ENST00000580139.1	TSL:2	n.198-1960C>A		intron	N/A

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

GnomAD2 exomes AF: 0.0631 AC: 15468 AN: 245234 AF XY: 0.0606

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 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

African (AFR) AF: 0.135 AC: 4526 AN: 33444

American (AMR) AF: 0.0863 AC: 3854 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 640 AN: 26074

East Asian (EAS) AF: 0.00766 AC: 304 AN: 39668

South Asian (SAS) AF: 0.0510 AC: 4393 AN: 86150

European-Finnish (FIN) AF: 0.0611 AC: 3239 AN: 53022

Middle Eastern (MID) AF: 0.0436 AC: 244 AN: 5594

European-Non Finnish (NFE) AF: 0.0608 AC: 67518 AN: 1111284

Other (OTH) AF: 0.0578 AC: 3484 AN: 60286

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

African (AFR) AF: 0.134 AC: 5580 AN: 41554

American (AMR) AF: 0.0972 AC: 1486 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0236 AC: 82 AN: 3470

East Asian (EAS) AF: 0.00696 AC: 36 AN: 5170

South Asian (SAS) AF: 0.0481 AC: 232 AN: 4828

European-Finnish (FIN) AF: 0.0605 AC: 643 AN: 10620

Middle Eastern (MID) AF: 0.0616 AC: 18 AN: 292

European-Non Finnish (NFE) AF: 0.0626 AC: 4257 AN: 68006

Other (OTH) AF: 0.0724 AC: 153 AN: 2112

Alfa AF: 0.0556 Hom.: 168

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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).

May 17, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

May 06, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Hypertrophic cardiomyopathy Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.15
DANN	Benign	0.61
PhyloP100		-0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9964300; hg19: chr18-3215030;