18-3176042-C-T

Variant names:

• chr18-3176042-C-T
• rs8099021
• NM_003803.4:c.1022G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003803.4(MYOM1):​c.1022G>A​(p.Gly341Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000284 in 1,408,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G341A) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: MYOM1 NM_003803.4 missense, splice_region
• Scores: Splicing: ADA: 0.9997
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.168

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.1022G>A	p.Gly341Glu	missense_variant, splice_region_variant	Exon 6 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.1022G>A	p.Gly341Glu	missense_variant, splice_region_variant	Exon 6 of 38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.1022G>A	p.Gly341Glu	missense_variant, splice_region_variant	Exon 6 of 37	1		ENSP00000261606.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000284 AC: 4 AN: 1408462 Hom.: 0 Cov.: 25 AF XY: 0.00000284 AC XY: 2 AN XY: 703850

Gnomad4 AFR exome AF: 0.00

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: 0.00000376

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Uncertain:1

Sep 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 341 of the MYOM1 protein (p.Gly341Glu). This variant also falls at the last nucleotide of exon 6, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MYOM1-related conditions. An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The glutamic acid amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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	0.50
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Benign	0.35
DEOGEN2	Benign	0.036	T;.;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.19	T;T;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.089	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.12	N;.;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	1.5	N;.;N
REVEL	Benign	0.17
Sift	Benign	0.60	T;.;T
Sift4G	Benign	0.10	T;T;T
Polyphen		0.0	B;.;B
Vest4		0.12
MutPred		0.68		Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);
MVP		0.71
MPC		0.18
ClinPred		0.018	T
GERP RS		2.0
Varity_R		0.10
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
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

Other links and lift over

dbSNP: rs8099021; hg19: chr18-3176040;