rs199817096

chr18-3119878-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003803.4(MYOM1):c.3109G>A(p.Ala1037Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000436 in 1,606,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1037A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 6.00

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13221365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.3109G>A	p.Ala1037Thr	missense_variant	20/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.3109G>A	p.Ala1037Thr	missense_variant	20/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.2821G>A	p.Ala941Thr	missense_variant	19/37	1		A2	P52179-2

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000772

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000607

AC:

AN:

246940

Hom.:

AF XY:

0.0000373

AC XY:

AN XY:

133956

show subpopulations

Gnomad AFR exome

AF:

0.000909

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000892

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000234

AC:

AN:

1454156

Hom.:

Cov.:

AF XY:

0.0000194

AC XY:

AN XY:

722152

show subpopulations

Gnomad4 AFR exome

AF:

0.000781

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000452

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.000236

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.000867

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000277

Hom.:

Bravo

AF:

0.000151

ESP6500AA

AF:

0.00125

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000744

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000595

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2022

The c.3109G>A (p.A1037T) alteration is located in exon 20 (coding exon 19) of the MYOM1 gene. This alteration results from a G to A substitution at nucleotide position 3109, causing the alanine (A) at amino acid position 1037 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hypertrophic cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 27, 2023

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1037 of the MYOM1 protein (p.Ala1037Thr). This variant is present in population databases (rs199817096, gnomAD 0.06%), and has an allele count higher than expected for a pathogenic variant. 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: 454445). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MYOM1 protein function with a positive predictive value of 80%. 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

Benign

0.18

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.38

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.055

T;.;.

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.86

D;D;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.13

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.13

N;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.9

N;.;N

REVEL

Benign

0.096

Sift

Benign

0.38

T;.;T

Sift4G

Benign

0.27

T;T;T

Polyphen

0.97

D;.;D

Vest4

0.52

MVP

0.81

MPC

0.32

ClinPred

0.11

GERP RS

4.4

Varity_R

0.20

gMVP

0.56

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

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