rs2230165

Variant names:

• chr18-3188875-G-A
• rs2230165
• NM_003803.4:c.644C>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.644C>T​(p.Thr215Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0584 in 1,612,858 control chromosomes in the GnomAD database, including 3,226 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. T215R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.075 (535 hom., cov: 30)
  • Exomes 𝑓: 0.057 (2691 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0990
• 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=0.001524508).
• BP6: Variant 18-3188875-G-A is Benign according to our data. Variant chr18-3188875-G-A is described in ClinVar as Benign. ClinVar VariationId is 226832.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MYOM1	NM_003803.4	MANE Select	c.644C>T	p.Thr215Met	missense	Exon 4 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.644C>T	p.Thr215Met	missense	Exon 4 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.644C>T	p.Thr215Met	missense	Exon 4 of 38	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.644C>T	p.Thr215Met	missense	Exon 4 of 37	ENSP00000261606.7

Frequencies

GnomAD3 genomes AF: 0.0751 AC: 11357 AN: 151310 Hom.: 538 Cov.: 30

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0567

Gnomad ASJ AF: 0.0950

Gnomad EAS AF: 0.000781

Gnomad SAS AF: 0.0668

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.0796

Gnomad NFE AF: 0.0545

Gnomad OTH AF: 0.0788

GnomAD2 exomes AF: 0.0533 AC: 13270 AN: 248848 AF XY: 0.0536

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0342

Gnomad ASJ exome AF: 0.0882

Gnomad EAS exome AF: 0.000167

Gnomad FIN exome AF: 0.0298

Gnomad NFE exome AF: 0.0554

Gnomad OTH exome AF: 0.0530

GnomAD4 exome AF: 0.0567 AC: 82908 AN: 1461430 Hom.: 2691 Cov.: 32 AF XY: 0.0565 AC XY: 41104 AN XY: 727008

African (AFR) AF: 0.137 AC: 4577 AN: 33406

American (AMR) AF: 0.0360 AC: 1611 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0898 AC: 2348 AN: 26136

East Asian (EAS) AF: 0.000302 AC: 12 AN: 39698

South Asian (SAS) AF: 0.0626 AC: 5396 AN: 86252

European-Finnish (FIN) AF: 0.0287 AC: 1534 AN: 53384

Middle Eastern (MID) AF: 0.0795 AC: 458 AN: 5762

European-Non Finnish (NFE) AF: 0.0568 AC: 63167 AN: 1111728

Other (OTH) AF: 0.0630 AC: 3805 AN: 60350

GnomAD4 genome AF: 0.0750 AC: 11354 AN: 151428 Hom.: 535 Cov.: 30 AF XY: 0.0739 AC XY: 5459 AN XY: 73918

African (AFR) AF: 0.135 AC: 5544 AN: 41216

American (AMR) AF: 0.0566 AC: 859 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.0950 AC: 329 AN: 3462

East Asian (EAS) AF: 0.000783 AC: 4 AN: 5108

South Asian (SAS) AF: 0.0669 AC: 320 AN: 4784

European-Finnish (FIN) AF: 0.0301 AC: 315 AN: 10472

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.0545 AC: 3698 AN: 67902

Other (OTH) AF: 0.0780 AC: 164 AN: 2102

Alfa AF: 0.0632 Hom.: 686

Bravo AF: 0.0799

TwinsUK AF: 0.0583 AC: 216

ALSPAC AF: 0.0532 AC: 205

ESP6500AA AF: 0.130 AC: 531

ESP6500EA AF: 0.0586 AC: 490

ExAC AF: 0.0566 AC: 6837

EpiCase AF: 0.0593

EpiControl AF: 0.0595

ClinVar

ClinVar submissions as Germline

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	MYOM1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	5.2
DANN	Uncertain	0.98
DEOGEN2	Benign	0.014	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.54	T
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.099
PrimateAI	Benign	0.36	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.015
Sift	Benign	0.13	T
Sift4G	Benign	0.30	T
Polyphen		0.90	P
Vest4		0.11
MPC		0.22
ClinPred		0.0025	T
Varity_R		0.041
gMVP		0.20
Mutation Taster		=99/1	polymorphism (auto)

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: rs2230165; hg19: chr18-3188873; COSMIC: COSV55297516; COSMIC: COSV55297516;