6-7579990-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_004415.4(DSP):​c.3800G>C​(p.Arg1267Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1267Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

4
12
3

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.29

Publications

0 publications found
Variant links:
Genes affected
DSP (HGNC:3052): (desmoplakin) This gene encodes a protein that anchors intermediate filaments to desmosomal plaques and forms an obligate component of functional desmosomes. Mutations in this gene are the cause of several cardiomyopathies and keratodermas, including skin fragility-woolly hair syndrome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]
DSP Gene-Disease associations (from GenCC):
  • arrhythmogenic right ventricular dysplasia 8
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
  • keratosis palmoplantaris striata 2
    Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
  • skin fragility-woolly hair-palmoplantar keratoderma syndrome
    Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
  • arrhythmogenic cardiomyopathy with wooly hair and keratoderma
    Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
  • cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis
    Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
  • lethal acantholytic epidermolysis bullosa
    Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
  • familial isolated dilated cardiomyopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • striate palmoplantar keratoderma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • severe dermatitis-multiple allergies-metabolic wasting syndrome
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
  • hypertrophic cardiomyopathy
    Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.837

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DSPNM_004415.4 linkc.3800G>C p.Arg1267Pro missense_variant Exon 23 of 24 ENST00000379802.8 NP_004406.2 P15924-1B4DKX6
DSPNM_001319034.2 linkc.3800G>C p.Arg1267Pro missense_variant Exon 23 of 24 NP_001305963.1 P15924-3B4DKX6
DSPNM_001008844.3 linkc.3582+218G>C intron_variant Intron 23 of 23 NP_001008844.1 P15924-2B4DKX6Q4LE79

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
DSPENST00000379802.8 linkc.3800G>C p.Arg1267Pro missense_variant Exon 23 of 24 1 NM_004415.4 ENSP00000369129.3 P15924-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461848
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
727222
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86256
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53378
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
8.99e-7
AC:
1
AN:
1112012
Other (OTH)
AF:
0.00
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.75
D
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.84
T
M_CAP
Uncertain
0.20
D
MetaRNN
Pathogenic
0.84
D
MetaSVM
Uncertain
0.65
D
MutationAssessor
Uncertain
2.3
M
PhyloP100
4.3
PrimateAI
Uncertain
0.55
T
PROVEAN
Uncertain
-4.1
D
REVEL
Uncertain
0.61
Sift
Benign
0.050
D
Sift4G
Uncertain
0.0040
D
Polyphen
1.0
D
Vest4
0.79
MutPred
0.23
Loss of MoRF binding (P = 0.0465);
MVP
0.77
MPC
1.0
ClinPred
0.98
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.81
gMVP
0.83
Mutation Taster
=51/49
polymorphism

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

Other links and lift over

dbSNP: rs759698959; hg19: chr6-7580223; API