NM_003803.4:c.541T>C

Variant names:

• chr18-3188978-A-G
• rs1962519
• NM_003803.4:c.541T>C

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.541T>C​(p.Ser181Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.429 in 1,612,490 control chromosomes in the GnomAD database, including 155,065 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.38 (12112 hom., cov: 28)
  • Exomes 𝑓: 0.43 (142953 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.196
• Publications: 31 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=9.0599656E-7).
• BP6: Variant 18-3188978-A-G is Benign according to our data. Variant chr18-3188978-A-G is described in ClinVar as Benign. ClinVar VariationId is 226830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 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.541T>C	p.Ser181Pro	missense	Exon 4 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.541T>C	p.Ser181Pro	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.541T>C	p.Ser181Pro	missense	Exon 4 of 38	ENSP00000348821.4	P52179-1
	MYOM1	ENST00000261606.11	TSL:1	c.541T>C	p.Ser181Pro	missense	Exon 4 of 37	ENSP00000261606.7	P52179-2
	MYOM1	ENST00000941943.1		c.541T>C	p.Ser181Pro	missense	Exon 4 of 38	ENSP00000612002.1

Frequencies

GnomAD3 genomes AF: 0.378 AC: 56923 AN: 150678 Hom.: 12103 Cov.: 28

Gnomad AFR AF: 0.205

Gnomad AMI AF: 0.458

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.395

Gnomad EAS AF: 0.821

Gnomad SAS AF: 0.481

Gnomad FIN AF: 0.490

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.420

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.444 AC: 110640 AN: 249218 AF XY: 0.447

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.400

Gnomad ASJ exome AF: 0.392

Gnomad EAS exome AF: 0.821

Gnomad FIN exome AF: 0.504

Gnomad NFE exome AF: 0.417

Gnomad OTH exome AF: 0.423

GnomAD4 exome AF: 0.435 AC: 635354 AN: 1461694 Hom.: 142953 Cov.: 82 AF XY: 0.436 AC XY: 316962 AN XY: 727128

African (AFR) AF: 0.201 AC: 6716 AN: 33480

American (AMR) AF: 0.402 AC: 17975 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.392 AC: 10245 AN: 26134

East Asian (EAS) AF: 0.832 AC: 33021 AN: 39700

South Asian (SAS) AF: 0.473 AC: 40816 AN: 86258

European-Finnish (FIN) AF: 0.502 AC: 26791 AN: 53402

Middle Eastern (MID) AF: 0.278 AC: 1603 AN: 5768

European-Non Finnish (NFE) AF: 0.425 AC: 472075 AN: 1111856

Other (OTH) AF: 0.433 AC: 26112 AN: 60374

GnomAD4 genome AF: 0.378 AC: 56967 AN: 150796 Hom.: 12112 Cov.: 28 AF XY: 0.383 AC XY: 28128 AN XY: 73532

African (AFR) AF: 0.206 AC: 8443 AN: 41062

American (AMR) AF: 0.392 AC: 5923 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1367 AN: 3458

East Asian (EAS) AF: 0.822 AC: 4139 AN: 5034

South Asian (SAS) AF: 0.483 AC: 2303 AN: 4772

European-Finnish (FIN) AF: 0.490 AC: 5044 AN: 10286

Middle Eastern (MID) AF: 0.207 AC: 61 AN: 294

European-Non Finnish (NFE) AF: 0.420 AC: 28478 AN: 67774

Other (OTH) AF: 0.379 AC: 796 AN: 2098

Alfa AF: 0.412 Hom.: 62382

Bravo AF: 0.361

TwinsUK AF: 0.405 AC: 1501

ALSPAC AF: 0.426 AC: 1641

ESP6500AA AF: 0.187 AC: 747

ESP6500EA AF: 0.415 AC: 3467

ExAC AF: 0.437 AC: 52817

Asia WGS AF: 0.614 AC: 2132 AN: 3478

EpiCase AF: 0.402

EpiControl AF: 0.392

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T
Eigen	Benign	-0.45
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.68	T
MetaRNN	Benign	9.1e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.20
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.049
Sift	Benign	0.088	T
Sift4G	Benign	0.20	T
Polyphen		0.86	P
Vest4		0.33
MPC		0.18
ClinPred		0.018	T
GERP RS		1.3
Varity_R		0.25
gMVP		0.061
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: rs1962519; hg19: chr18-3188976; COSMIC: COSV55291896; COSMIC: COSV55291896;