18-3071880-C-T

Position:

chr18-3071880-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003803.4(MYOM1):c.4718G>A(p.Arg1573Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,604,694 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 7 hom., cov: 32)

Exomes 𝑓: 0.0018 ( 52 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 7.66

Variant links:

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 links:

MYOM1 (HGNC:):

MYOM1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009976715).

BP6

Variant 18-3071880-C-T is Benign according to our data. Variant chr18-3071880-C-T is described in ClinVar as [Benign]. Clinvar id is 226827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3071880-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00319 (485/152266) while in subpopulation AMR AF= 0.0232 (354/15290). AF 95% confidence interval is 0.0212. There are 7 homozygotes in gnomad4. There are 242 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.4718G>A	p.Arg1573Gln	missense_variant	37/38	ENST00000356443.9	NP_003794.3	P52179-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.4718G>A	p.Arg1573Gln	missense_variant	37/38	1	NM_003803.4	ENSP00000348821.4	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.4430G>A	p.Arg1477Gln	missense_variant	36/37	1		ENSP00000261606.7	P52179-2
MYOM1	ENST00000581804.1 linkuse as main transcript	n.208G>A		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes

AF:

0.00317

AC:

482

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0230

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0143

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000294

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00758

AC:

1771

AN:

233670

Hom.:

AF XY:

0.00578

AC XY:

729

AN XY:

126142

show subpopulations

Gnomad AFR exome

AF:

0.000785

Gnomad AMR exome

AF:

0.0430

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0168

Gnomad SAS exome

AF:

0.000429

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000105

Gnomad OTH exome

AF:

0.00452

GnomAD4 exome

AF:

0.00181

AC:

2624

AN:

1452428

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1116

AN XY:

721354

show subpopulations

Gnomad4 AFR exome

AF:

0.000601

Gnomad4 AMR exome

AF:

0.0417

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0148

Gnomad4 SAS exome

AF:

0.000298

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000488

Gnomad4 OTH exome

AF:

0.00201

GnomAD4 genome

AF:

0.00319

AC:

485

AN:

152266

Hom.:

Cov.:

AF XY:

0.00325

AC XY:

242

AN XY:

74438

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.0232

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0143

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000294

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00116

Hom.:

Bravo

AF:

0.00563

ESP6500AA

AF:

0.000498

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00519

AC:

628

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

Arg1573Gln in exon 37 of MYOM1: This variant is not expected to have clinical si gnificance because it has been identified in 4.5% (6/132) of Mexican chromosomes from a broad population by the 1000 Genomes Project (http://www.ncbi.nlm.nih.go v/projects/SNP; dbSNP rs117342470). -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Hypertrophic cardiomyopathy

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 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

0.24

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Uncertain

-0.070

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.25

T;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

MetaRNN

Benign

0.010

T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.4

M;.;.

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-2.9

D;.;D

REVEL

Uncertain

0.31

Sift

Uncertain

0.0050

D;.;D

Sift4G

Uncertain

0.0080

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.88

MVP

0.80

MPC

0.67

ClinPred

0.023

GERP RS

4.9

Varity_R

0.71

gMVP

0.65

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over