chr18-3126717-C-T

Variant names:

• chr18-3126717-C-T
• rs751491766
• NM_003803.4:c.2975G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003803.4(MYOM1):​c.2975G>A​(p.Ser992Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S992I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.71
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003803.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.2975G>A	p.Ser992Asn	missense	Exon 19 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.2687G>A	p.Ser896Asn	missense	Exon 18 of 37	NP_062830.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	ENST00000356443.9	TSL:1 MANE Select	c.2975G>A	p.Ser992Asn	missense	Exon 19 of 38	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.2687G>A	p.Ser896Asn	missense	Exon 18 of 37	ENSP00000261606.7
	MYOM1	ENST00000941943.1		c.2939G>A	p.Ser980Asn	missense	Exon 19 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.052	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.020	T
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.4	L
PhyloP100		4.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Benign	0.30	T
Sift4G	Benign	0.11	T
Polyphen		0.99	D
Vest4		0.44
MutPred		0.65		Loss of phosphorylation at Y996 (P = 0.1071)
MVP		0.88
MPC		0.56
ClinPred		0.94	D
GERP RS		5.4
Varity_R		0.48
gMVP		0.43
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs751491766; hg19: chr18-3126715;