chr18-3168818-G-A

Position:

chr18-3168818-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_003803.4(MYOM1):c.1338C>T(p.Asn446=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.269 in 1,612,432 control chromosomes in the GnomAD database, including 59,073 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.28 ( 5861 hom., cov: 32)

Exomes 𝑓: 0.27 ( 53212 hom. )

Consequence

MYOM1
NM_003803.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0006205

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.58

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP6

Variant 18-3168818-G-A is Benign according to our data. Variant chr18-3168818-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226799.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=2.58 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.317 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.1338C>T	p.Asn446=	splice_region_variant, synonymous_variant	9/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.1338C>T	p.Asn446=	splice_region_variant, synonymous_variant	9/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.1338C>T	p.Asn446=	splice_region_variant, synonymous_variant	9/37	1		A2	P52179-2

Frequencies

GnomAD3 genomes

AF:

0.276

AC:

41969

AN:

151842

Hom.:

5849

Cov.:

show subpopulations

Gnomad AFR

AF:

0.321

Gnomad AMI

AF:

0.218

Gnomad AMR

AF:

0.234

Gnomad ASJ

AF:

0.276

Gnomad EAS

AF:

0.285

Gnomad SAS

AF:

0.279

Gnomad FIN

AF:

0.231

Gnomad MID

AF:

0.222

Gnomad NFE

AF:

0.266

Gnomad OTH

AF:

0.276

GnomAD3 exomes

AF:

0.257

AC:

63820

AN:

248584

Hom.:

8372

AF XY:

0.258

AC XY:

34746

AN XY:

134844

show subpopulations

Gnomad AFR exome

AF:

0.323

Gnomad AMR exome

AF:

0.187

Gnomad ASJ exome

AF:

0.271

Gnomad EAS exome

AF:

0.279

Gnomad SAS exome

AF:

0.283

Gnomad FIN exome

AF:

0.225

Gnomad NFE exome

AF:

0.263

Gnomad OTH exome

AF:

0.265

GnomAD4 exome

AF:

0.268

AC:

391441

AN:

1460470

Hom.:

53212

Cov.:

AF XY:

0.268

AC XY:

194893

AN XY:

726560

show subpopulations

Gnomad4 AFR exome

AF:

0.322

Gnomad4 AMR exome

AF:

0.190

Gnomad4 ASJ exome

AF:

0.273

Gnomad4 EAS exome

AF:

0.318

Gnomad4 SAS exome

AF:

0.279

Gnomad4 FIN exome

AF:

0.234

Gnomad4 NFE exome

AF:

0.268

Gnomad4 OTH exome

AF:

0.269

GnomAD4 genome

AF:

0.277

AC:

42025

AN:

151962

Hom.:

5861

Cov.:

AF XY:

0.273

AC XY:

20270

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.322

Gnomad4 AMR

AF:

0.234

Gnomad4 ASJ

AF:

0.276

Gnomad4 EAS

AF:

0.285

Gnomad4 SAS

AF:

0.279

Gnomad4 FIN

AF:

0.231

Gnomad4 NFE

AF:

0.266

Gnomad4 OTH

AF:

0.279

Alfa

AF:

0.265

Hom.:

9383

Bravo

AF:

0.275

Asia WGS

AF:

0.283

AC:

984

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Oct 29, 2014	p.Asn446Asn in exon 9 of MYOM1: This variant is not expected to have clinical si gnificance because it has been identified in 31% (1167/3758) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS/; dbSNP rs2230167). -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.93

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00062

dbscSNV1_RF

Benign

0.042

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over