18-3090722-C-T
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_003803.4(MYOM1):c.3945G>A(p.Thr1315=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,613,878 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.0091 ( 17 hom., cov: 31)
Exomes 𝑓: 0.00094 ( 17 hom. )
Consequence
MYOM1
NM_003803.4 synonymous
NM_003803.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.717
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.56).
BP6
Variant 18-3090722-C-T is Benign according to our data. Variant chr18-3090722-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 226820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-0.717 with no splicing effect.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0091 (1385/152210) while in subpopulation AFR AF= 0.0316 (1312/41530). AF 95% confidence interval is 0.0302. There are 17 homozygotes in gnomad4. There are 647 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 17 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MYOM1 | NM_003803.4 | c.3945G>A | p.Thr1315= | synonymous_variant | 27/38 | ENST00000356443.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MYOM1 | ENST00000356443.9 | c.3945G>A | p.Thr1315= | synonymous_variant | 27/38 | 1 | NM_003803.4 | P2 | |
MYOM1 | ENST00000261606.11 | c.3657G>A | p.Thr1219= | synonymous_variant | 26/37 | 1 | A2 | ||
MYOM1 | ENST00000581075.1 | c.45G>A | p.Thr15= | synonymous_variant, NMD_transcript_variant | 1/8 | 5 |
Frequencies
GnomAD3 genomes AF: 0.00910 AC: 1384AN: 152092Hom.: 17 Cov.: 31
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GnomAD3 exomes AF: 0.00232 AC: 579AN: 249236Hom.: 9 AF XY: 0.00179 AC XY: 242AN XY: 135202
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GnomAD4 exome AF: 0.000944 AC: 1380AN: 1461668Hom.: 17 Cov.: 30 AF XY: 0.000821 AC XY: 597AN XY: 727110
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GnomAD4 genome AF: 0.00910 AC: 1385AN: 152210Hom.: 17 Cov.: 31 AF XY: 0.00870 AC XY: 647AN XY: 74410
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 17, 2022 | 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. - |
Benign, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Nov 24, 2014 | Thr1315Thr in exon 27 of MYOM1: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue and is not located wi thin the splice consensus sequence. It has been identified in 3.1% (122/3948) of African American chromosomes from a broad population by the NHLBI Exome Sequenc ing Project (http://evs.gs.washington.edu/EVS; dbSNP rs75748615). - |
Hypertrophic cardiomyopathy Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
Computational scores
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BayesDel_noAF
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CADD
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DANN
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at