chr18-3215232-C-T

Variant names:

• chr18-3215232-C-T
• rs1662315
• NM_003803.4:c.-9G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003803.4(MYOM1):​c.-9G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,598,040 control chromosomes in the GnomAD database, including 52,778 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.26 (5726 hom., cov: 32)
  • Exomes 𝑓: 0.24 (47052 hom.)
• Consequence: MYOM1 NM_003803.4 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.601
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.-9G>A		5_prime_UTR_variant	Exon 2 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.-9G>A		5_prime_UTR_variant	Exon 2 of 38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.-9G>A		5_prime_UTR_variant	Exon 2 of 37	1		ENSP00000261606.7
ENSG00000265399	ENST00000580139.1	n.198-1760C>T		intron_variant	Intron 2 of 4	2

Frequencies

GnomAD3 genomes AF: 0.264 AC: 40197 AN: 151996 Hom.: 5731 Cov.: 32

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.226

Gnomad ASJ AF: 0.240

Gnomad EAS AF: 0.619

Gnomad SAS AF: 0.274

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.243

GnomAD2 exomes AF: 0.265 AC: 60250 AN: 227484 AF XY: 0.264

Gnomad AFR exome AF: 0.292

Gnomad AMR exome AF: 0.200

Gnomad ASJ exome AF: 0.247

Gnomad EAS exome AF: 0.625

Gnomad FIN exome AF: 0.269

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.247

GnomAD4 exome AF: 0.245 AC: 354050 AN: 1445926 Hom.: 47052 Cov.: 34 AF XY: 0.245 AC XY: 175749 AN XY: 717178

African (AFR) AF: 0.298 AC: 9905 AN: 33188

American (AMR) AF: 0.205 AC: 8745 AN: 42656

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 6365 AN: 25794

East Asian (EAS) AF: 0.648 AC: 25345 AN: 39136

South Asian (SAS) AF: 0.261 AC: 22020 AN: 84424

European-Finnish (FIN) AF: 0.262 AC: 13784 AN: 52602

Middle Eastern (MID) AF: 0.246 AC: 1412 AN: 5740

European-Non Finnish (NFE) AF: 0.228 AC: 251135 AN: 1102590

Other (OTH) AF: 0.257 AC: 15339 AN: 59796

GnomAD4 genome AF: 0.264 AC: 40199 AN: 152114 Hom.: 5726 Cov.: 32 AF XY: 0.267 AC XY: 19873 AN XY: 74358

African (AFR) AF: 0.296 AC: 12282 AN: 41500

American (AMR) AF: 0.226 AC: 3451 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.240 AC: 834 AN: 3472

East Asian (EAS) AF: 0.620 AC: 3203 AN: 5170

South Asian (SAS) AF: 0.274 AC: 1319 AN: 4820

European-Finnish (FIN) AF: 0.263 AC: 2784 AN: 10596

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15450 AN: 67972

Other (OTH) AF: 0.239 AC: 504 AN: 2112

Alfa AF: 0.240 Hom.: 7409

Bravo AF: 0.265

Asia WGS AF: 0.400 AC: 1392 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Nov 24, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

-9G>A in exon 2 of MYOM1: This variant is not expected to have clinical signific ance because it has been identified in 27.9% (1141/4096) of African American chr omosomes from a broad population by the NHLBI Exome Sequencing Project (http://e vs.gs.washington.edu/EVS; dbSNP rs1662315). -

MYOM1-related disorder Benign:1

Oct 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	15
DANN	Benign	0.83
PhyloP100		0.60
Mutation Taster		=300/0	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: rs1662315; hg19: chr18-3215230;