6-7585346-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004415.4(DSP):c.8084T>G(p.Phe2695Cys) 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 1,461,882 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F2695Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.08

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.8084T>G	p.Phe2695Cys	missense_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.6755T>G	p.Phe2252Cys	missense_variant	24/24
DSP	NM_001008844.3	c.6287T>G	p.Phe2096Cys	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.8084T>G	p.Phe2695Cys	missense_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.6287T>G	p.Phe2096Cys	missense_variant	24/24	1		A2
DSP	ENST00000710359.1	c.6755T>G	p.Phe2252Cys	missense_variant	24/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461882 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 01, 2021

This sequence change replaces phenylalanine with cysteine at codon 2695 of the DSP protein (p.Phe2695Cys). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with DSP-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
Cadd	Benign	23
Dann	Benign	0.95
DEOGEN2	Pathogenic	0.80	D;.
Eigen	Benign	0.17
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.5	D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;.
Vest4		0.80
MutPred		0.49		Gain of ubiquitination at K2693 (P = 0.0747);.;
MVP		0.67
MPC		0.87
ClinPred		0.98	D
GERP RS		2.9
Varity_R		0.87
gMVP		0.79

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: rs764994940; hg19: chr6-7585579;