18-3215232-C-T

Position:

• chr18-3215232-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000356443.9(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. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.26 (5726 hom., cov: 32)
  • Exomes 𝑓: 0.24 (47052 hom.)
• Consequence: MYOM1 ENST00000356443.9 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.601

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 18-3215232-C-T is Benign according to our data. Variant chr18-3215232-C-T is described in ClinVar as [Benign]. Clinvar id is 226839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.-9G>A		5_prime_UTR_variant	2/38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.-9G>A		5_prime_UTR_variant	2/38	1	NM_003803.4	ENSP00000348821	P2
MYOM1	ENST00000261606.11	c.-9G>A		5_prime_UTR_variant	2/37	1		ENSP00000261606	A2
	ENST00000580139.1	n.198-1760C>T		intron_variant, non_coding_transcript_variant		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

GnomAD3 exomes AF: 0.265 AC: 60250 AN: 227484 Hom.: 9207 AF XY: 0.264 AC XY: 32512 AN XY: 123358

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 SAS exome AF: 0.261

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

Gnomad4 AFR exome AF: 0.298

Gnomad4 AMR exome AF: 0.205

Gnomad4 ASJ exome AF: 0.247

Gnomad4 EAS exome AF: 0.648

Gnomad4 SAS exome AF: 0.261

Gnomad4 FIN exome AF: 0.262

Gnomad4 NFE exome AF: 0.228

Gnomad4 OTH exome AF: 0.257

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

Gnomad4 AFR AF: 0.296

Gnomad4 AMR AF: 0.226

Gnomad4 ASJ AF: 0.240

Gnomad4 EAS AF: 0.620

Gnomad4 SAS AF: 0.274

Gnomad4 FIN AF: 0.263

Gnomad4 NFE AF: 0.227

Gnomad4 OTH AF: 0.239

Alfa AF: 0.235 Hom.: 4940

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 10, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

-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

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

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

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: rs1662315; hg19: chr18-3215230;