rs202145133

Variant names:

• chr18-3215085-T-C
• rs202145133
• NM_003803.4:c.139A>G

Variant summary

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

The ENST00000356443.9(MYOM1):​c.139A>G​(p.Ser47Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00622 in 1,613,626 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (61 hom.)
• Consequence: MYOM1 ENST00000356443.9 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.14
• Publications: 10 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

ENSG00000265399 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047293007).
• BP6: Variant 18-3215085-T-C is Benign according to our data. Variant chr18-3215085-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 226801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 1007 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.139A>G	p.Ser47Gly	missense	Exon 2 of 38	NP_003794.3
	MYOM1	NM_019856.2		c.139A>G	p.Ser47Gly	missense	Exon 2 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.139A>G	p.Ser47Gly	missense	Exon 2 of 38	ENSP00000348821.4
	MYOM1	ENST00000261606.11	TSL:1	c.139A>G	p.Ser47Gly	missense	Exon 2 of 37	ENSP00000261606.7
	ENSG00000265399	ENST00000580139.1	TSL:2	n.198-1907T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00662 AC: 1008 AN: 152182 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.000868

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0420

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00663 AC: 1639 AN: 247328 AF XY: 0.00641

Gnomad AFR exome AF: 0.000722

Gnomad AMR exome AF: 0.00128

Gnomad ASJ exome AF: 0.0158

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0372

Gnomad NFE exome AF: 0.00527

Gnomad OTH exome AF: 0.00734

GnomAD4 exome AF: 0.00618 AC: 9028 AN: 1461326 Hom.: 61 Cov.: 33 AF XY: 0.00611 AC XY: 4439 AN XY: 726988

African (AFR) AF: 0.000508 AC: 17 AN: 33476

American (AMR) AF: 0.00150 AC: 67 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.0151 AC: 395 AN: 26116

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86254

European-Finnish (FIN) AF: 0.0388 AC: 2062 AN: 53156

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5754

European-Non Finnish (NFE) AF: 0.00543 AC: 6034 AN: 1111816

Other (OTH) AF: 0.00731 AC: 441 AN: 60348

GnomAD4 genome AF: 0.00661 AC: 1007 AN: 152300 Hom.: 13 Cov.: 32 AF XY: 0.00791 AC XY: 589 AN XY: 74462

African (AFR) AF: 0.000865 AC: 36 AN: 41596

American (AMR) AF: 0.00183 AC: 28 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.0173 AC: 60 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.0420 AC: 446 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00626 AC: 426 AN: 68016

Other (OTH) AF: 0.00473 AC: 10 AN: 2114

Alfa AF: 0.00526 Hom.: 13

Bravo AF: 0.00324

ESP6500AA AF: 0.000983 AC: 4

ESP6500EA AF: 0.00251 AC: 21

ExAC AF: 0.00529 AC: 640

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00513

EpiControl AF: 0.00379

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.018
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.75	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.1
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.052
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.045	D
Polyphen		0.20	B
Vest4		0.36
MVP		0.78
MPC		0.13
ClinPred		0.0097	T
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.54
Mutation Taster		=95/5	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: rs202145133; hg19: chr18-3215083; COSMIC: COSV106083479;