rs199900004

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 2P and 12B. PM2BP4_StrongBP6_Very_Strong

The NM_003803.4(MYOM1):ā€‹c.2656A>Gā€‹(p.Ser886Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00097 in 1,614,010 control chromosomes in the GnomAD database, including 1 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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00051 ( 0 hom., cov: 32)
Exomes š‘“: 0.0010 ( 1 hom. )

Consequence

MYOM1
NM_003803.4 missense

Scores

19

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.926
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.036579847).
BP6
Variant 18-3129370-T-C is Benign according to our data. Variant chr18-3129370-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 227698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr18-3129370-T-C is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MYOM1NM_003803.4 linkuse as main transcriptc.2656A>G p.Ser886Gly missense_variant 18/38 ENST00000356443.9 NP_003794.3 P52179-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MYOM1ENST00000356443.9 linkuse as main transcriptc.2656A>G p.Ser886Gly missense_variant 18/381 NM_003803.4 ENSP00000348821.4 P52179-1
MYOM1ENST00000261606.11 linkuse as main transcriptc.2506+2005A>G intron_variant 1 ENSP00000261606.7 P52179-2
MYOM1ENST00000582016.1 linkuse as main transcriptn.212A>G non_coding_transcript_exon_variant 1/34

Frequencies

GnomAD3 genomes
AF:
0.000506
AC:
77
AN:
152188
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000660
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000911
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000590
AC:
147
AN:
249258
Hom.:
0
AF XY:
0.000614
AC XY:
83
AN XY:
135220
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000145
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000229
Gnomad FIN exome
AF:
0.00102
Gnomad NFE exome
AF:
0.000965
Gnomad OTH exome
AF:
0.000661
GnomAD4 exome
AF:
0.00102
AC:
1489
AN:
1461704
Hom.:
1
Cov.:
31
AF XY:
0.000974
AC XY:
708
AN XY:
727134
show subpopulations
Gnomad4 AFR exome
AF:
0.0000597
Gnomad4 AMR exome
AF:
0.000201
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.000267
Gnomad4 FIN exome
AF:
0.00120
Gnomad4 NFE exome
AF:
0.00122
Gnomad4 OTH exome
AF:
0.000530
GnomAD4 genome
AF:
0.000506
AC:
77
AN:
152306
Hom.:
0
Cov.:
32
AF XY:
0.000510
AC XY:
38
AN XY:
74480
show subpopulations
Gnomad4 AFR
AF:
0.000120
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000660
Gnomad4 NFE
AF:
0.000911
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000899
Hom.:
0
Bravo
AF:
0.000484
TwinsUK
AF:
0.00162
AC:
6
ALSPAC
AF:
0.00
AC:
0
ESP6500AA
AF:
0.000525
AC:
2
ESP6500EA
AF:
0.000972
AC:
8
ExAC
AF:
0.000563
AC:
68
Asia WGS
AF:
0.000289
AC:
1
AN:
3478
EpiCase
AF:
0.00158
EpiControl
AF:
0.000533

ClinVar

Significance: Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineMay 26, 2015p.Ser886Gly in exon 18 of MYOM1: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 4 mammals (alpaca, Bactrian camel, cape golden mole and platypus) have a g lycine (Gly) at this position despite high nearby amino acid conservation. It h as been identified in 0.1% (59/66740) of European chromosomes by the Exome Aggre gation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs199900004). -
not provided Benign:1
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Hypertrophic cardiomyopathy Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 22, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.51
T
BayesDel_noAF
Benign
-0.53
CADD
Benign
18
DANN
Benign
0.77
DEOGEN2
Benign
0.014
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.1
FATHMM_MKL
Benign
0.21
N
LIST_S2
Benign
0.44
T
M_CAP
Benign
0.0090
T
MetaRNN
Benign
0.037
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.90
L
PrimateAI
Benign
0.30
T
PROVEAN
Benign
-0.35
N
REVEL
Benign
0.048
Sift
Benign
0.29
T
Sift4G
Benign
0.24
T
Polyphen
0.0
B
Vest4
0.23
MVP
0.35
MPC
0.14
ClinPred
0.042
T
GERP RS
-6.0
Varity_R
0.063
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs199900004; hg19: chr18-3129368; API