rs180910875

Variant names:

• chr18-3135575-C-T
• rs180910875
• NM_003803.4:c.2181G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003803.4(MYOM1):​c.2181G>A​(p.Thr727Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,613,696 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00090 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0018 (7 hom.)
• Consequence: MYOM1 NM_003803.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.24
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 18-3135575-C-T is Benign according to our data. Variant chr18-3135575-C-T is described in ClinVar as Benign. ClinVar VariationId is 239570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.24 with no splicing effect.
• BS2: High AC in GnomAd4 at 137 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.2181G>A	p.Thr727Thr	synonymous	Exon 15 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.2181G>A	p.Thr727Thr	synonymous	Exon 15 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.2181G>A	p.Thr727Thr	synonymous	Exon 15 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.2181G>A	p.Thr727Thr	synonymous	Exon 15 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.2181G>A	p.Thr727Thr	synonymous	Exon 15 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.000901 AC: 137 AN: 151994 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00146

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000860 AC: 214 AN: 248960 AF XY: 0.000888

Gnomad AFR exome AF: 0.000776

Gnomad AMR exome AF: 0.000464

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00135

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.00184 AC: 2693 AN: 1461584 Hom.: 7 Cov.: 30 AF XY: 0.00184 AC XY: 1336 AN XY: 727056

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39692

South Asian (SAS) AF: 0.000939 AC: 81 AN: 86226

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53398

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00220 AC: 2442 AN: 1111814

Other (OTH) AF: 0.00202 AC: 122 AN: 60362

GnomAD4 genome AF: 0.000901 AC: 137 AN: 152112 Hom.: 1 Cov.: 31 AF XY: 0.000753 AC XY: 56 AN XY: 74354

African (AFR) AF: 0.000554 AC: 23 AN: 41488

American (AMR) AF: 0.000197 AC: 3 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10586

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00146 AC: 99 AN: 68008

Other (OTH) AF: 0.00190 AC: 4 AN: 2106

Alfa AF: 0.00103 Hom.: 0

Bravo AF: 0.000895

EpiCase AF: 0.000872

EpiControl AF: 0.00154

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	MYOM1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.2
DANN	Benign	0.41
PhyloP100		-3.2
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs180910875; hg19: chr18-3135573; COSMIC: COSV105059011;