rs142735495

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_003803.4(MYOM1):​c.590C>T​(p.Thr197Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00138 in 1,612,030 control chromosomes in the GnomAD database, including 33 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. T197T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00097 ( 1 hom., cov: 30)
Exomes 𝑓: 0.0014 ( 32 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

18

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -1.17

Publications

6 publications found
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 Gene-Disease associations (from GenCC):
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0035447478).
BP6
Variant 18-3188929-G-A is Benign according to our data. Variant chr18-3188929-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 226831.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS2
High AC in GnomAd4 at 147 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
MYOM1NM_003803.4 linkc.590C>T p.Thr197Met missense_variant Exon 4 of 38 ENST00000356443.9 NP_003794.3 P52179-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
MYOM1ENST00000356443.9 linkc.590C>T p.Thr197Met missense_variant Exon 4 of 38 1 NM_003803.4 ENSP00000348821.4 P52179-1
MYOM1ENST00000261606.11 linkc.590C>T p.Thr197Met missense_variant Exon 4 of 37 1 ENSP00000261606.7 P52179-2

Frequencies

GnomAD3 genomes
AF:
0.000973
AC:
147
AN:
151138
Hom.:
1
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.0000976
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00126
Gnomad ASJ
AF:
0.00173
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.0138
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00633
Gnomad NFE
AF:
0.000648
Gnomad OTH
AF:
0.00288
GnomAD2 exomes
AF:
0.00243
AC:
605
AN:
249230
AF XY:
0.00318
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.000492
Gnomad ASJ exome
AF:
0.00407
Gnomad EAS exome
AF:
0.0000556
Gnomad FIN exome
AF:
0.000278
Gnomad NFE exome
AF:
0.00108
Gnomad OTH exome
AF:
0.00182
GnomAD4 exome
AF:
0.00142
AC:
2075
AN:
1460774
Hom.:
32
Cov.:
32
AF XY:
0.00184
AC XY:
1337
AN XY:
726686
show subpopulations
African (AFR)
AF:
0.0000601
AC:
2
AN:
33270
American (AMR)
AF:
0.000626
AC:
28
AN:
44706
Ashkenazi Jewish (ASJ)
AF:
0.00475
AC:
124
AN:
26132
East Asian (EAS)
AF:
0.0000252
AC:
1
AN:
39698
South Asian (SAS)
AF:
0.0131
AC:
1131
AN:
86226
European-Finnish (FIN)
AF:
0.000243
AC:
13
AN:
53398
Middle Eastern (MID)
AF:
0.00693
AC:
40
AN:
5768
European-Non Finnish (NFE)
AF:
0.000553
AC:
614
AN:
1111242
Other (OTH)
AF:
0.00202
AC:
122
AN:
60334
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.472
Heterozygous variant carriers
0
149
299
448
598
747
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
32
64
96
128
160
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.000972
AC:
147
AN:
151256
Hom.:
1
Cov.:
30
AF XY:
0.00125
AC XY:
92
AN XY:
73856
show subpopulations
African (AFR)
AF:
0.0000973
AC:
4
AN:
41118
American (AMR)
AF:
0.00126
AC:
19
AN:
15116
Ashkenazi Jewish (ASJ)
AF:
0.00173
AC:
6
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5080
South Asian (SAS)
AF:
0.0136
AC:
65
AN:
4784
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10492
Middle Eastern (MID)
AF:
0.0102
AC:
3
AN:
294
European-Non Finnish (NFE)
AF:
0.000648
AC:
44
AN:
67892
Other (OTH)
AF:
0.00285
AC:
6
AN:
2102
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.507
Heterozygous variant carriers
0
8
16
23
31
39
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00151
Hom.:
3
Bravo
AF:
0.000695
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000835
AC:
7
ExAC
AF:
0.00246
AC:
297
Asia WGS
AF:
0.00289
AC:
10
AN:
3478
EpiCase
AF:
0.00120
EpiControl
AF:
0.00136

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Oct 27, 2022
Ambry Genetics
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Jun 10, 2015
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

p.Thr197Met in exon 4 of MYOM1: This variant is not expected to have clinical si gnificance because it has been identified in 1.3% (215/16512) of South Asian chr omosomes, including 4 homozygotes, by the Exome Aggregation Consortium (ExAC, ht tp://exac.broadinstitute.org; dbSNP rs142735495). -

not provided Benign:1
-
Breakthrough Genomics, Breakthrough Genomics
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:not provided

- -

Hypertrophic cardiomyopathy Benign:1
Jan 23, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.25
BayesDel_addAF
Benign
-0.65
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
0.35
DANN
Benign
0.67
DEOGEN2
Benign
0.015
T;.;.
Eigen
Benign
-1.7
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.0084
N
LIST_S2
Benign
0.44
T;T;T
MetaRNN
Benign
0.0035
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N;.;N
PhyloP100
-1.2
PrimateAI
Benign
0.23
T
PROVEAN
Benign
0.51
N;.;N
REVEL
Benign
0.021
Sift
Benign
0.25
T;.;T
Sift4G
Benign
0.11
T;T;T
Polyphen
0.40
B;.;P
Vest4
0.078
MVP
0.35
MPC
0.14
ClinPred
0.010
T
GERP RS
-1.6
Varity_R
0.014
gMVP
0.16
Mutation Taster
=99/1
polymorphism

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

Other links and lift over

dbSNP: rs142735495; hg19: chr18-3188927; COSMIC: COSV99865246; COSMIC: COSV99865246; API