rs1554108700

Positions:

• chr6-7583158-C-G

Variant summary

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

The NM_004415.4(DSP):​c.5896C>G​(p.Leu1966Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L1966L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.15

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 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.5896C>G	p.Leu1966Val	missense_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2	c.4567C>G	p.Leu1523Val	missense_variant	24/24
DSP	NM_001008844.3	c.4099C>G	p.Leu1367Val	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.5896C>G	p.Leu1966Val	missense_variant	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.4099C>G	p.Leu1367Val	missense_variant	24/24	1		A2
DSP	ENST00000710359.1	c.4567C>G	p.Leu1523Val	missense_variant	24/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 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: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Sep 04, 2023

This missense variant replaces leucine with valine at codon 1966 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with DSP-related disorders in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 28, 2021

This sequence change replaces leucine with valine at codon 1966 of the DSP protein (p.Leu1966Val). The leucine residue is highly conserved and there is a small physicochemical difference between leucine and valine. 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 are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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	Benign	0.17
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.94	D;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.92	D;N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0070	D;D
Sift4G	Benign	0.075	T;T
Polyphen		0.95	P;.
Vest4		0.55
MutPred		0.38		Gain of methylation at K1965 (P = 0.0361);.;
MVP		0.51
MPC		0.82
ClinPred		0.82	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.40

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: rs1554108700; hg19: chr6-7583391;