rs191505313

Positions:

• chr18-3188947-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000356443.9(MYOM1):​c.572C>T​(p.Thr191Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0003 in 1,600,572 control chromosomes in the GnomAD database, including 4 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 Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. T191T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00030 (4 hom.)
• Consequence: MYOM1 ENST00000356443.9 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.160

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0052524507).
• BP6: Variant 18-3188947-G-A is Benign according to our data. Variant chr18-3188947-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 525076.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4	c.572C>T	p.Thr191Met	missense_variant	4/38	ENST00000356443.9	NP_003794.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9	c.572C>T	p.Thr191Met	missense_variant	4/38	1	NM_003803.4	ENSP00000348821	P2
MYOM1	ENST00000261606.11	c.572C>T	p.Thr191Met	missense_variant	4/37	1		ENSP00000261606	A2

Frequencies

GnomAD3 genomes AF: 0.000292 AC: 44 AN: 150818 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000440

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000132

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000198

Gnomad SAS AF: 0.00356

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000884

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000546 AC: 136 AN: 249246 Hom.: 0 AF XY: 0.000710 AC XY: 96 AN XY: 135218

Gnomad AFR exome AF: 0.000517

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00353

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000133

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000301 AC: 436 AN: 1449634 Hom.: 4 Cov.: 32 AF XY: 0.000435 AC XY: 314 AN XY: 721390

Gnomad4 AFR exome AF: 0.000151

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000510

Gnomad4 SAS exome AF: 0.00383

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.0000726

Gnomad4 OTH exome AF: 0.000184

GnomAD4 genome AF: 0.000292 AC: 44 AN: 150938 Hom.: 0 Cov.: 30 AF XY: 0.000339 AC XY: 25 AN XY: 73672

Gnomad4 AFR AF: 0.000439

Gnomad4 AMR AF: 0.000132

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000199

Gnomad4 SAS AF: 0.00356

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000884

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000189 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.000491 AC: 2

ESP6500EA AF: 0.000119 AC: 1

ExAC AF: 0.000628 AC: 76

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	13
DANN	Benign	0.85
DEOGEN2	Benign	0.015	T;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.68	T;T;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.010	N;.;N
REVEL	Benign	0.072
Sift	Uncertain	0.013	D;.;D
Sift4G	Benign	0.097	T;T;T
Polyphen		0.34	B;.;B
Vest4		0.14
MVP		0.34
MPC		0.14
ClinPred		0.014	T
GERP RS		1.5
Varity_R		0.017
gMVP		0.14

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: rs191505313; hg19: chr18-3188945;