rs199531701

Variant names:

• chr18-3067359-G-A
• rs199531701
• NM_003803.4:c.4961C>T

Your query was ambiguous. Multiple possible variants found:

• chr18-3067359-G-A
• chr18-3067359-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000356443.9(MYOM1):​c.4961C>T​(p.Ser1654Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000181 in 1,612,622 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S1654S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: MYOM1 ENST00000356443.9 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 8.12
• Publications: 2 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.012505442).
• BP6: Variant 18-3067359-G-A is Benign according to our data. Variant chr18-3067359-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416035.
• BS2: High AC in GnomAd4 at 35 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000356443.9. 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.4961C>T	p.Ser1654Leu	missense	Exon 38 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.4673C>T	p.Ser1558Leu	missense	Exon 37 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.4961C>T	p.Ser1654Leu	missense	Exon 38 of 38	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.4673C>T	p.Ser1558Leu	missense	Exon 37 of 37	ENSP00000261606.7
	MYOM1	ENST00000581804.1	TSL:3	n.451C>T		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.000223 AC: 34 AN: 152178 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000947 AC: 237 AN: 250206 AF XY: 0.000702

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.00672

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000176 AC: 257 AN: 1460326 Hom.: 1 Cov.: 33 AF XY: 0.000135 AC XY: 98 AN XY: 726458

African (AFR) AF: 0.0000598 AC: 2 AN: 33434

American (AMR) AF: 0.00552 AC: 247 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86190

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4642

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111860

Other (OTH) AF: 0.0000830 AC: 5 AN: 60240

GnomAD4 genome AF: 0.000230 AC: 35 AN: 152296 Hom.: 1 Cov.: 33 AF XY: 0.000242 AC XY: 18 AN XY: 74464

African (AFR) AF: 0.000289 AC: 12 AN: 41568

American (AMR) AF: 0.00150 AC: 23 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000909 Hom.: 0

Bravo AF: 0.000495

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000684 AC: 83

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	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	0.33
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.1
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.22
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.082	T
Polyphen		0.85	P
Vest4		0.14
MVP		0.77
MPC		0.26
ClinPred		0.068	T
GERP RS		4.7
Varity_R		0.30
gMVP		0.55
Mutation Taster		=85/15	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: rs199531701; hg19: chr18-3067357; COSMIC: COSV55290926;