18-3086141-A-T

Variant names:

• chr18-3086141-A-T
• rs374491316
• NM_003803.4:c.4148T>A

Variant summary

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

The NM_003803.4(MYOM1):​c.4148T>A​(p.Ile1383Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as not provided (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 9.29

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.4148T>A	p.Ile1383Asn	missense_variant	Exon 30 of 38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.4148T>A	p.Ile1383Asn	missense_variant	Exon 30 of 38	1	NM_003803.4	ENSP00000348821.4
MYOM1	ENST00000261606.11	c.3860T>A	p.Ile1287Asn	missense_variant	Exon 29 of 37	1		ENSP00000261606.7
MYOM1	ENST00000581075.1	n.248T>A		non_coding_transcript_exon_variant	Exon 4 of 8	5		ENSP00000462039.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

MYOM1-related disorder Other:1

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GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.040
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;.
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.080	D
MetaRNN	Uncertain	0.58	D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.7	L;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.7	D;.;D
REVEL	Uncertain	0.55
Sift	Uncertain	0.014	D;.;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.59
MutPred		0.53		Loss of stability (P = 0.0274);.;.;
MVP		0.90
MPC		0.84
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.75

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: rs374491316; hg19: chr18-3086139;