18-3176042-C-G

Position:

chr18-3176042-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_003803.4(MYOM1):c.1022G>C(p.Gly341Ala) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.726 in 1,549,978 control chromosomes in the GnomAD database, including 410,464 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.75 ( 42873 hom., cov: 32)

Exomes 𝑓: 0.72 ( 367591 hom. )

Consequence

MYOM1
NM_003803.4 missense, splice_region

Scores

Splicing: ADA: 0.9992

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.168

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 -16 ACMG points.

BP6

Variant 18-3176042-C-G is Benign according to our data. Variant chr18-3176042-C-G is described in ClinVar as [Benign]. Clinvar id is 226796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.795 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.1022G>C	p.Gly341Ala	missense_variant, splice_region_variant	6/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.1022G>C	p.Gly341Ala	missense_variant, splice_region_variant	6/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.1022G>C	p.Gly341Ala	missense_variant, splice_region_variant	6/37	1		A2	P52179-2

Frequencies

GnomAD3 genomes

AF:

0.749

AC:

113909

AN:

152052

Hom.:

42804

Cov.:

show subpopulations

Gnomad AFR

AF:

0.802

Gnomad AMI

AF:

0.733

Gnomad AMR

AF:

0.751

Gnomad ASJ

AF:

0.695

Gnomad EAS

AF:

0.762

Gnomad SAS

AF:

0.784

Gnomad FIN

AF:

0.765

Gnomad MID

AF:

0.691

Gnomad NFE

AF:

0.714

Gnomad OTH

AF:

0.746

GnomAD3 exomes

AF:

0.742

AC:

182610

AN:

245946

Hom.:

68048

AF XY:

0.741

AC XY:

98922

AN XY:

133428

show subpopulations

Gnomad AFR exome

AF:

0.805

Gnomad AMR exome

AF:

0.775

Gnomad ASJ exome

AF:

0.695

Gnomad EAS exome

AF:

0.751

Gnomad SAS exome

AF:

0.796

Gnomad FIN exome

AF:

0.771

Gnomad NFE exome

AF:

0.708

Gnomad OTH exome

AF:

0.727

GnomAD4 exome

AF:

0.724

AC:

1011443

AN:

1397806

Hom.:

367591

Cov.:

AF XY:

0.725

AC XY:

506872

AN XY:

698758

show subpopulations

Gnomad4 AFR exome

AF:

0.803

Gnomad4 AMR exome

AF:

0.771

Gnomad4 ASJ exome

AF:

0.694

Gnomad4 EAS exome

AF:

0.786

Gnomad4 SAS exome

AF:

0.793

Gnomad4 FIN exome

AF:

0.770

Gnomad4 NFE exome

AF:

0.710

Gnomad4 OTH exome

AF:

0.721

GnomAD4 genome

AF:

0.749

AC:

114035

AN:

152172

Hom.:

42873

Cov.:

AF XY:

0.750

AC XY:

55790

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.802

Gnomad4 AMR

AF:

0.751

Gnomad4 ASJ

AF:

0.695

Gnomad4 EAS

AF:

0.762

Gnomad4 SAS

AF:

0.784

Gnomad4 FIN

AF:

0.765

Gnomad4 NFE

AF:

0.714

Gnomad4 OTH

AF:

0.749

Alfa

AF:

0.711

Hom.:

26400

Bravo

AF:

0.749

TwinsUK

AF:

0.717

AC:

2660

ALSPAC

AF:

0.724

AC:

2790

ESP6500AA

AF:

0.808

AC:

3239

ESP6500EA

AF:

0.716

AC:

5968

ExAC

AF:

0.738

AC:

89145

Asia WGS

AF:

0.803

AC:

2790

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Nov 26, 2014	This is a RefSeq error. The reference base (c.1022G) is the minor allele. This a llele (G) has been identified in 28% (2372/8340) of European American chromosome s and 19% (769/4008) of African American chromosomes by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS/; dbSNP rs8099021) and thus meets c riteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 07, 2019	This alteration is classified as 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

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.31

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

DANN

Benign

0.22

DEOGEN2

Benign

0.035

T;.;.

Eigen

Benign

-0.89

Eigen_PC

Benign

-0.79

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.055

T;T;T

MetaRNN

Benign

8.3e-7

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.62

N;.;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.24

PROVEAN

Benign

0.65

N;.;N

REVEL

Benign

0.16

Sift

Benign

0.80

T;.;T

Sift4G

Benign

0.14

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.051

MPC

0.15

ClinPred

0.0035

GERP RS

2.0

Varity_R

0.11

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.75

SpliceAI score (max)

0.030

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