chr18-3094252-C-A

Variant names:

• chr18-3094252-C-A
• rs374656485
• NM_003803.4:c.3782G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003803.4(MYOM1):​c.3782G>T​(p.Arg1261Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.91

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.825

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.3782G>T	p.Arg1261Leu	missense_variant	Exon 26 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.3782G>T	p.Arg1261Leu	missense_variant	Exon 26 of 38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.3494G>T	p.Arg1165Leu	missense_variant	Exon 25 of 37	1		ENSP00000261606.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.70
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.98	D;D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.9	M;.;.
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-6.6	D;.;D
REVEL	Uncertain	0.55
Sift	Benign	0.076	T;.;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.91
MutPred		0.47		Loss of MoRF binding (P = 0.0021);.;.;
MVP		0.55
MPC		0.69
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.80
gMVP		0.82

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

Other links and lift over

dbSNP: rs374656485; hg19: chr18-3094250; COSMIC: COSV55292509; COSMIC: COSV55292509;