rs142735495

Variant names:

• chr18-3188929-G-A
• rs142735495
• NM_003803.4:c.590C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003803.4(MYOM1):​c.590C>T​(p.Thr197Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,612,030 control chromosomes in the GnomAD database, including 33 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T197T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00097 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0014 (32 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.17
• Publications: 6 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035447478).
• BP6: Variant 18-3188929-G-A is Benign according to our data. Variant chr18-3188929-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 147 AD gene.

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.590C>T	p.Thr197Met	missense	Exon 4 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.590C>T	p.Thr197Met	missense	Exon 4 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.590C>T	p.Thr197Met	missense	Exon 4 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.590C>T	p.Thr197Met	missense	Exon 4 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.590C>T	p.Thr197Met	missense	Exon 4 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.000973 AC: 147 AN: 151138 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.0000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00126

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0138

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000648

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.00243 AC: 605 AN: 249230 AF XY: 0.00318

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.000492

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.0000556

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00108

Gnomad OTH exome AF: 0.00182

GnomAD4 exome AF: 0.00142 AC: 2075 AN: 1460774 Hom.: 32 Cov.: 32 AF XY: 0.00184 AC XY: 1337 AN XY: 726686

African (AFR) AF: 0.0000601 AC: 2 AN: 33270

American (AMR) AF: 0.000626 AC: 28 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00475 AC: 124 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0131 AC: 1131 AN: 86226

European-Finnish (FIN) AF: 0.000243 AC: 13 AN: 53398

Middle Eastern (MID) AF: 0.00693 AC: 40 AN: 5768

European-Non Finnish (NFE) AF: 0.000553 AC: 614 AN: 1111242

Other (OTH) AF: 0.00202 AC: 122 AN: 60334

GnomAD4 genome AF: 0.000972 AC: 147 AN: 151256 Hom.: 1 Cov.: 30 AF XY: 0.00125 AC XY: 92 AN XY: 73856

African (AFR) AF: 0.0000973 AC: 4 AN: 41118

American (AMR) AF: 0.00126 AC: 19 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5080

South Asian (SAS) AF: 0.0136 AC: 65 AN: 4784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10492

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000648 AC: 44 AN: 67892

Other (OTH) AF: 0.00285 AC: 6 AN: 2102

Alfa AF: 0.00151 Hom.: 3

Bravo AF: 0.000695

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000835 AC: 7

ExAC AF: 0.00246 AC: 297

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00136

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.35
DANN	Benign	0.67
DEOGEN2	Benign	0.015	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0084	N
LIST_S2	Benign	0.44	T
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-1.2
PrimateAI	Benign	0.23	T
PROVEAN	Benign	0.51	N
REVEL	Benign	0.021
Sift	Benign	0.25	T
Sift4G	Benign	0.11	T
Polyphen		0.40	B
Vest4		0.078
MVP		0.35
MPC		0.14
ClinPred		0.010	T
GERP RS		-1.6
Varity_R		0.014
gMVP		0.16
Mutation Taster		=99/1	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: rs142735495; hg19: chr18-3188927; COSMIC: COSV99865246; COSMIC: COSV99865246;