rs1461028383

Positions:

• chr6-7583005-C-A
• chr6-7583005-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_004415.4(DSP):​c.5743C>A​(p.Arg1915Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1915H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.16

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.052740604).
• BP6: Variant 6-7583005-C-A is Benign according to our data. Variant chr6-7583005-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2925014.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.5743C>A	p.Arg1915Ser	missense_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.4414C>A	p.Arg1472Ser	missense_variant	24/24
DSP	NM_001008844.3	c.3946C>A	p.Arg1316Ser	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.5743C>A	p.Arg1915Ser	missense_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3946C>A	p.Arg1316Ser	missense_variant	24/24	1		A2
DSP	ENST00000710359.1	c.4414C>A	p.Arg1472Ser	missense_variant	24/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251140 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135764

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.82
DEOGEN2	Benign	0.19	T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.053	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.23	N;.
MutationTaster	Benign	0.94	N;N
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-0.25	N;N
REVEL	Benign	0.049
Sift	Benign	0.35	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.012	B;.
Vest4		0.19
MutPred		0.20		Gain of phosphorylation at R1915 (P = 0.0013);.;
MVP		0.34
MPC		0.25
ClinPred		0.028	T
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.067
gMVP		0.32

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

Other links and lift over

dbSNP: rs1461028383; hg19: chr6-7583238;