rs121913005

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_001927.4(DES):c.1325C>A(p.Thr442Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000476 in 1,595,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T442I) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000051 ( 0 hom. )

Consequence

DES
NM_001927.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 4.86

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]

DES links:

DES (HGNC:):

DES links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1

In a region_of_interest Interaction with CRYAB (size 15) in uniprot entity DESM_HUMAN there are 14 pathogenic changes around while only 0 benign (100%) in NM_001927.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-219425699-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.34050092).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DES	NM_001927.4 linkuse as main transcript	c.1325C>A	p.Thr442Asn	missense_variant	8/9	ENST00000373960.4	NP_001918.3	P17661Q53SB5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DES	ENST00000373960.4 linkuse as main transcript	c.1325C>A	p.Thr442Asn	missense_variant	8/9	1	NM_001927.4	ENSP00000363071.3		P17661

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151928

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000449

AC:

AN:

222748

Hom.:

AF XY:

0.00000838

AC XY:

AN XY:

119348

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000100

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000506

AC:

AN:

1443900

Hom.:

Cov.:

AF XY:

0.0000531

AC XY:

AN XY:

716136

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000662

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

151928

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74184

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Desmin-related myofibrillar myopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 04, 2023

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 442 of the DES protein (p.Thr442Asn). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 626715). 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. This variant disrupts the p.Thr442 amino acid residue in DES. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 17221859, 18653338, 21262226, 22153487, 22215463). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 19, 2023

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Jul 04, 2022

- -

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

Nov 21, 2021

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2021

Has not been previously published as pathogenic or benign to our knowledge; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 626715; Landrum et al., 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 26582918, 27535533) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 05, 2019

The p.T442N variant (also known as c.1325C>A), located in coding exon 8 of the DES gene, results from a C to A substitution at nucleotide position 1325. The threonine at codon 442 is replaced by asparagine, an amino acid with similar properties. A different variant affecting this codon (p.T442I, c.1325C>T) has been reported in association with desminopathy with cardiac and skeletal system involvement (Bär H et al. Hum. Mutat., 2007 Apr;28:374-86). This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

CardioboostCm

Benign

0.0030

BayesDel_addAF

Pathogenic

0.19

BayesDel_noAF

Uncertain

0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.12

MetaRNN

Benign

0.34

MetaSVM

Uncertain

0.78

MutationAssessor

Benign

1.4

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.5

REVEL

Uncertain

0.47

Sift

Benign

0.21

Sift4G

Benign

0.30

Polyphen

0.41

Vest4

0.44

MutPred

0.34

Loss of catalytic residue at K443 (P = 0.039);

MVP

0.98

MPC

0.61

ClinPred

0.55

GERP RS

4.5

Varity_R

0.20

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over