rs200179081

chr18-3141941-T-Cchr18-3141941-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP6

The NM_003803.4(MYOM1):c.2023A>G(p.Lys675Glu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000589 in 1,613,758 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00062 ( 0 hom. )

Consequence

MYOM1
NM_003803.4 missense, splice_region

Scores

Splicing: ADA: 0.2811

Clinical Significance

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

Conservation

PhyloP100: 8.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 18-3141941-T-C is Benign according to our data. Variant chr18-3141941-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 410251.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MYOM1	NM_003803.4 linkuse as main transcript	c.2023A>G	p.Lys675Glu	missense_variant, splice_region_variant	14/38	ENST00000356443.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MYOM1	ENST00000356443.9 linkuse as main transcript	c.2023A>G	p.Lys675Glu	missense_variant, splice_region_variant	14/38	1	NM_003803.4	P2	P52179-1
MYOM1	ENST00000261606.11 linkuse as main transcript	c.2023A>G	p.Lys675Glu	missense_variant, splice_region_variant	14/37	1		A2	P52179-2
MYOM1	ENST00000577294.1 linkuse as main transcript	n.79A>G		splice_region_variant, non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000321

AC:

AN:

249080

Hom.:

AF XY:

0.000348

AC XY:

AN XY:

135140

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000656

Gnomad OTH exome

AF:

0.000496

GnomAD4 exome

AF:

0.000620

AC:

906

AN:

1461474

Hom.:

Cov.:

AF XY:

0.000602

AC XY:

438

AN XY:

727026

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.000787

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.000289

AC:

AN:

152284

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.000544

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000487

Hom.:

Bravo

AF:

0.000268

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00104

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000481

AC:

ExAC

AF:

0.000356

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000474

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

Jul 27, 2023

The p.K675E variant (also known as c.2023A>G), located in coding exon 13 of the MYOM1 gene, results from an A to G substitution at nucleotide position 2023. The lysine at codon 675 is replaced by glutamic acid, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Uncertain

0.038

BayesDel_noAF

Pathogenic

0.18

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.;.

Eigen

Pathogenic

0.84

Eigen_PC

Pathogenic

0.81

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Uncertain

0.099

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

3.2

M;.;M

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Uncertain

-3.6

D;.;D

REVEL

Uncertain

0.50

Sift

Uncertain

0.0070

D;.;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.84

MVP

0.94

MPC

0.72

ClinPred

0.36

GERP RS

5.8

Varity_R

0.70

gMVP

0.83

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.28

dbscSNV1_RF

Benign

0.37

SpliceAI score (max)

0.010

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