18-3176072-C-T

Position:

chr18-3176072-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003803.4(MYOM1):c.992G>A(p.Arg331Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00028 in 1,605,286 control chromosomes in the GnomAD database, including 3 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 Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00028 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00028 ( 3 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 5.65

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00949505).

BP6

Variant 18-3176072-C-T is Benign according to our data. Variant chr18-3176072-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 525111.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.992G>A	p.Arg331Gln	missense_variant	6/38	ENST00000356443.9	NP_003794.3	P52179-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.992G>A	p.Arg331Gln	missense_variant	6/38	1	NM_003803.4	ENSP00000348821.4		P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.992G>A	p.Arg331Gln	missense_variant	6/37	1		ENSP00000261606.7		P52179-2

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000494

AC:

123

AN:

248988

Hom.:

AF XY:

0.000422

AC XY:

AN XY:

135098

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.00945

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.000280

AC:

407

AN:

1453180

Hom.:

Cov.:

AF XY:

0.000261

AC XY:

189

AN XY:

723518

show subpopulations

Gnomad4 AFR exome

AF:

0.0000300

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0110

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000489

Gnomad4 OTH exome

AF:

0.000898

GnomAD4 genome

AF:

0.000276

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000283

AC XY:

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000553

Hom.:

Bravo

AF:

0.000404

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000605

AC:

ExAC

AF:

0.000356

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 19, 2022

The c.992G>A (p.R331Q) alteration is located in exon 6 (coding exon 5) of the MYOM1 gene. This alteration results from a G to A substitution at nucleotide position 992, causing the arginine (R) at amino acid position 331 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.045

T;.;.

Eigen

Benign

0.15

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

D;D;D

M_CAP

Benign

0.026

MetaRNN

Benign

0.0095

T;T;T

MetaSVM

Benign

-0.75

MutationAssessor

Benign

0.45

N;.;N

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.1

N;.;N

REVEL

Benign

0.21

Sift

Benign

0.10

T;.;T

Sift4G

Benign

0.24

T;T;T

Polyphen

0.89

P;.;B

Vest4

0.51

MVP

0.83

MPC

0.26

ClinPred

0.075

GERP RS

5.9

Varity_R

0.19

gMVP

0.43

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