rs202145133

chr18-3215085-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003803.4(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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (13 hom., cov: 32)
  • Exomes 𝑓: 0.0062 (61 hom.)
• Consequence: MYOM1 NM_003803.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.14

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047293007).
• BS2: High Homozygotes in GnomAd at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4	c.139A>G	p.Ser47Gly	missense_variant	2/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9	c.139A>G	p.Ser47Gly	missense_variant	2/38	1	NM_003803.4	P2
MYOM1	ENST00000261606.11	c.139A>G	p.Ser47Gly	missense_variant	2/37	1		A2
	ENST00000580139.1	n.198-1907T>C		intron_variant, non_coding_transcript_variant		2

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

GnomAD3 exomes AF: 0.00663 AC: 1639 AN: 247328 Hom.: 17 AF XY: 0.00641 AC XY: 863 AN XY: 134668

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 SAS exome AF: 0.0000327

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

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00150

Gnomad4 ASJ exome AF: 0.0151

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.0388

Gnomad4 NFE exome AF: 0.00543

Gnomad4 OTH exome AF: 0.00731

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

Gnomad4 AFR AF: 0.000865

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.0173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0420

Gnomad4 NFE AF: 0.00626

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00545 Hom.: 10

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 24, 2014

Ser47Gly in exon 2 of MYOM1: This variant is not expected to have clinical signi ficance because it has been identified in 4.3% (8/186) of Finnish chromosomes fr om a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.gov/p rojects/SNP; dbSNP rs202145133). -

Hypertrophic cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2013

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance -

Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.51	D;D;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.92	N;N
REVEL	Benign	0.052
Sift	Uncertain	0.010	D;D
Sift4G	Uncertain	0.045	D;D
Polyphen		0.20	B;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs202145133; hg19: chr18-3215083;