rs1791085

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003803.4(MYOM1):c.64G>T(p.Val22Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,613,500 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V22G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.12

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:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.020968616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.64G>T	p.Val22Leu	missense_variant	2/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.64G>T	p.Val22Leu	missense_variant	2/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.64G>T	p.Val22Leu	missense_variant	2/37	1		A2	P52179-2
	ENST00000580139.1 linkuse as main transcript	n.198-1832C>A		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes

AF:

0.000184

AC:

AN:

152126

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000970

AC:

AN:

247380

Hom.:

AF XY:

0.0000595

AC XY:

AN XY:

134384

show subpopulations

Gnomad AFR exome

AF:

0.000457

Gnomad AMR exome

AF:

0.0000582

Gnomad ASJ exome

AF:

0.000400

Gnomad EAS exome

AF:

0.000392

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000357

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000684

AC:

100

AN:

1461256

Hom.:

Cov.:

AF XY:

0.0000550

AC XY:

AN XY:

726864

show subpopulations

Gnomad4 AFR exome

AF:

0.000448

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.000345

Gnomad4 EAS exome

AF:

0.000731

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000333

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000184

AC:

AN:

152244

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 18, 2023

This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 22 of the MYOM1 protein (p.Val22Leu). This variant is present in population databases (rs1791085, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with MYOM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 845126). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.65

DEOGEN2

Benign

0.014

T;.

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.42

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.021

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.7

N;N

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.40

PROVEAN

Benign

0.42

N;N

REVEL

Benign

0.086

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.054

MVP

0.45

MPC

0.14

ClinPred

0.0083

GERP RS

5.7

Varity_R

0.034

gMVP

0.35

Splicing

Name

Calibrated prediction

Score

Prediction

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