rs878854472

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000373960.4(DES):​c.524G>A​(p.Arg175His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000129 in 1,551,812 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R175R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

DES
ENST00000373960.4 missense

Scores

5
11
4

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 9.72
Variant links:
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]

Genome browser will be placed here

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, 0.873

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
DESNM_001927.4 linkuse as main transcriptc.524G>A p.Arg175His missense_variant 1/9 ENST00000373960.4 NP_001918.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
DESENST00000373960.4 linkuse as main transcriptc.524G>A p.Arg175His missense_variant 1/91 NM_001927.4 ENSP00000363071 P1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152176
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
7.14e-7
AC:
1
AN:
1399636
Hom.:
0
Cov.:
92
AF XY:
0.00
AC XY:
0
AN XY:
690666
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000126
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152176
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74332
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Desmin-related myofibrillar myopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 29, 2023In 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. 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. ClinVar contains an entry for this variant (Variation ID: 239077). This variant has not been reported in the literature in individuals affected with DES-related conditions. This variant is present in population databases (no rsID available, gnomAD 0.01%). This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 175 of the DES protein (p.Arg175His). -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicSep 17, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.18
CardioboostCm
Uncertain
0.20
BayesDel_addAF
Pathogenic
0.30
D
BayesDel_noAF
Pathogenic
0.19
CADD
Pathogenic
31
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.80
D
Eigen
Uncertain
0.48
Eigen_PC
Uncertain
0.53
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.94
D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.87
D
MetaSVM
Uncertain
0.62
D
MutationAssessor
Uncertain
2.5
M
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.79
T
PROVEAN
Uncertain
-3.5
D
REVEL
Pathogenic
0.80
Sift
Benign
0.051
T
Sift4G
Benign
0.072
T
Polyphen
0.40
B
Vest4
0.82
MutPred
0.72
Loss of MoRF binding (P = 0.0284);
MVP
0.95
MPC
1.4
ClinPred
0.99
D
GERP RS
4.6
Varity_R
0.52
gMVP
0.80

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs878854472; hg19: chr2-220283708; API