rs138375140

Positions:

chr18-3168934-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.1222G>A(p.Asp408Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,613,738 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 (★★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.56

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:

MYOM1 (HGNC:):

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=0.087007016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.1222G>A	p.Asp408Asn	missense_variant	9/38	ENST00000356443.9	NP_003794.3	P52179-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.1222G>A	p.Asp408Asn	missense_variant	9/38	1	NM_003803.4	ENSP00000348821.4		P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.1222G>A	p.Asp408Asn	missense_variant	9/37	1		ENSP00000261606.7		P52179-2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152156

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000403

AC:

AN:

248128

Hom.:

AF XY:

0.0000520

AC XY:

AN XY:

134630

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.0000267

Gnomad OTH exome

AF:

0.000498

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461464

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726986

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

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:

0.0000108

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000525

AC:

AN:

152274

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74446

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000843

Hom.:

Bravo

AF:

0.0000869

ExAC

AF:

0.00000828

AC:

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

Feb 16, 2023

The c.1222G>A (p.D408N) alteration is located in exon 9 (coding exon 8) of the MYOM1 gene. This alteration results from a G to A substitution at nucleotide position 1222, causing the aspartic acid (D) at amino acid position 408 to be replaced by an asparagine (N). 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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 12, 2024

This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 408 of the MYOM1 protein (p.Asp408Asn). This variant is present in population databases (rs138375140, gnomAD 0.006%). 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: 569222). 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 not expected to disrupt MYOM1 protein function with a negative 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

Uncertain

0.36

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.61

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.036

T;.;.

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.97

D;D;D

M_CAP

Benign

0.010

MetaRNN

Benign

0.087

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.90

N;.;N

PrimateAI

Uncertain

0.62

PROVEAN

Benign

-0.21

N;.;N

REVEL

Benign

0.15

Sift

Benign

0.049

D;.;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.85

P;.;P

Vest4

0.17

MVP

0.68

MPC

0.50

ClinPred

0.11

GERP RS

5.5

Varity_R

0.10

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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