rs9807556

Variant names:

• chr18-3151738-T-A
• rs9807556
• NM_003803.4:c.1799A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003803.4(MYOM1):​c.1799A>T​(p.Glu600Val) variant causes a missense change. The variant allele was found at a frequency of 0.00303 in 1,613,796 control chromosomes in the GnomAD database, including 123 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E600K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (77 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (46 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.99
• Publications: 7 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0089993775).
• BP6: Variant 18-3151738-T-A is Benign according to our data. Variant chr18-3151738-T-A is described in ClinVar as Benign. ClinVar VariationId is 226803.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0538 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.1799A>T	p.Glu600Val	missense	Exon 12 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.1799A>T	p.Glu600Val	missense	Exon 12 of 37	NP_062830.1	P52179-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	ENST00000356443.9	TSL:1 MANE Select	c.1799A>T	p.Glu600Val	missense	Exon 12 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.1799A>T	p.Glu600Val	missense	Exon 12 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.1799A>T	p.Glu600Val	missense	Exon 12 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2478 AN: 152094 Hom.: 77 Cov.: 32

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00759

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.00406 AC: 1012 AN: 249168 AF XY: 0.00301

Gnomad AFR exome AF: 0.0565

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000239

Gnomad OTH exome AF: 0.00265

GnomAD4 exome AF: 0.00164 AC: 2400 AN: 1461584 Hom.: 46 Cov.: 30 AF XY: 0.00144 AC XY: 1047 AN XY: 727062

African (AFR) AF: 0.0553 AC: 1852 AN: 33476

American (AMR) AF: 0.00349 AC: 156 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5766

European-Non Finnish (NFE) AF: 0.000142 AC: 158 AN: 1111780

Other (OTH) AF: 0.00369 AC: 223 AN: 60370

GnomAD4 genome AF: 0.0163 AC: 2484 AN: 152212 Hom.: 77 Cov.: 32 AF XY: 0.0157 AC XY: 1172 AN XY: 74418

African (AFR) AF: 0.0557 AC: 2314 AN: 41518

American (AMR) AF: 0.00758 AC: 116 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68010

Other (OTH) AF: 0.0161 AC: 34 AN: 2108

Alfa AF: 0.00261 Hom.: 9

Bravo AF: 0.0181

ESP6500AA AF: 0.0486 AC: 184

ESP6500EA AF: 0.000242 AC: 2

ExAC AF: 0.00496 AC: 599

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0090	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		4.0
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.3	D
REVEL	Benign	0.23
Sift	Benign	0.061	T
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.71
MVP		0.88
MPC		0.48
ClinPred		0.040	T
GERP RS		5.1
Varity_R		0.51
gMVP		0.69
Mutation Taster		=86/14	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: rs9807556; hg19: chr18-3151736;