rs144908941
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate
The NM_001927.4(DES):c.643G>A(p.Val215Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,614,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000018 ( 0 hom. )
Consequence
DES
NM_001927.4 missense
NM_001927.4 missense
Scores
9
8
3
Clinical Significance
Conservation
PhyloP100: 9.81
Genes affected
DES (HGNC:2770): (desmin) This gene encodes a muscle-specific class III intermediate filament. Homopolymers of this protein form a stable intracytoplasmic filamentous network connecting myofibrils to each other and to the plasma membrane. Mutations in this gene are associated with desmin-related myopathy, a familial cardiac and skeletal myopathy (CSM), and with distal myopathies. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.854
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
DES | NM_001927.4 | c.643G>A | p.Val215Met | missense_variant | 3/9 | ENST00000373960.4 | NP_001918.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
DES | ENST00000373960.4 | c.643G>A | p.Val215Met | missense_variant | 3/9 | 1 | NM_001927.4 | ENSP00000363071.3 | ||
DES | ENST00000477226.6 | n.117G>A | non_coding_transcript_exon_variant | 2/8 | 4 | |||||
DES | ENST00000492726.1 | n.38G>A | non_coding_transcript_exon_variant | 2/6 | 4 | |||||
DES | ENST00000683013.1 | n.31G>A | non_coding_transcript_exon_variant | 1/7 |
Frequencies
GnomAD3 genomes AF: 0.000145 AC: 22AN: 152202Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000596 AC: 15AN: 251468Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135912
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GnomAD4 exome AF: 0.0000185 AC: 27AN: 1461880Hom.: 0 Cov.: 35 AF XY: 0.0000165 AC XY: 12AN XY: 727238
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GnomAD4 genome AF: 0.000145 AC: 22AN: 152202Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74352
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:10Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 28, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Athena Diagnostics | Jan 28, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Aug 23, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Jan 07, 2022 | Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 222542) - |
Desmin-related myofibrillar myopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 20, 2024 | This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 215 of the DES protein (p.Val215Met). This variant is present in population databases (rs144908941, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DES-related conditions. ClinVar contains an entry for this variant (Variation ID: 222542). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on DES protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Dilated cardiomyopathy 1I Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | New York Genome Center | Dec 10, 2021 | The c.643G>A (p.Val215Met) variant identified in the DES gene substitutes a well conserved Valine for Methionine at amino acid 215/471 (exon 3/9).This variant is found with low frequency in gnomAD(v3.1.2)(22 heterozygotes, 0 homozygotes; allele frequency:1.45e-4) suggesting it is not a common benign variant in the populations represented in that database. In silico algorithms predict this variant to be Damaging (SIFT; score:0.028) and Pathogenic (REVEL; score:0.782) to the function of the canonical transcript. This variant is reported as a Variant of Uncertain Significance in ClinVar (VarID:222542), and to our current knowledge has not been reported in affected individuals in the literature. The p.Val215 residue is within Coil 1B domain of DES (UniProtKB:P17661). Given the lack of compelling evidence for its pathogenicity, the c.643G>A (p.Val215Met) variant identified in the DES gene is reported as a Variant of Uncertain Significance. - |
Desmin-related myofibrillar myopathy;C1858154:Dilated cardiomyopathy 1I;C1867005:Neurogenic scapuloperoneal syndrome, Kaeser type Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 24, 2021 | - - |
DES-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 10, 2023 | The DES c.643G>A variant is predicted to result in the amino acid substitution p.Val215Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.044% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-220284976-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Primary familial hypertrophic cardiomyopathy Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Blueprint Genetics | Aug 26, 2015 | - - |
Cardiovascular phenotype Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 09, 2022 | The p.V215M variant (also known as c.643G>A), located in coding exon 3 of the DES gene, results from a G to A substitution at nucleotide position 643. The valine at codon 215 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. 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. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 08, 2023 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
CardioboostCm
Benign
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Pathogenic
D
MutationAssessor
Uncertain
M
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D
REVEL
Pathogenic
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at