rs753855393

Positions:

• chr6-7566471-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM1 BP6

The NM_004415.4(DSP):​c.1034A>G​(p.Asp345Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000616 in 1,461,576 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 8.47

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a repeat Spectrin 2 (size 103) in uniprot entity DESP_HUMAN there are 6 pathogenic changes around while only 1 benign (86%) in NM_004415.4
• BP6: Variant 6-7566471-A-G is Benign according to our data. Variant chr6-7566471-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465878.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.1034A>G	p.Asp345Gly	missense_variant	8/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1034A>G	p.Asp345Gly	missense_variant	8/24		NP_001305963.1
DSP	NM_001008844.3	c.1034A>G	p.Asp345Gly	missense_variant	8/24		NP_001008844.1
DSP	NM_001406591.1	c.1034A>G	p.Asp345Gly	missense_variant	8/11		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1034A>G	p.Asp345Gly	missense_variant	8/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1034A>G	p.Asp345Gly	missense_variant	8/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1034A>G	p.Asp345Gly	missense_variant	8/24			ENSP00000518230.1
DSP	ENST00000682228.1	n.358A>G		non_coding_transcript_exon_variant	2/3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000479 AC: 12 AN: 250782 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135600

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461576 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727102

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000151

ExAC AF: 0.0000330 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jul 01, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Aug 01, 2017	Invitae performed testing for this patient. Given the lack of case data, frequency in gnomAD and type of variant, we consider this variant a variant of uncertain significance, probably benign and we do not feel it is suitable for assessing risk in healthy relatives ("predictive genetic testing"). I could find no reports of this variant in Google or PubMed. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change. It should be noted that few missense variants in DSP are thought to be pathogenic. ExAC constraints indicate this gene is tolerant to missense variation (Z=0.91). The variant has been seen in 12 of 122792 individuals listed in the Genome Aggregation Consortium Dataset (gnomAD; http://gnomad.broadinstitute.org/), which currently includes variant calls on >140,000 unrelated individuals of African, Asian, European, Latino, and Ashkenazi descent. The variant has been seen in 10 of 8614 East Asian Individuals (MAF = 0.058%). The site is well covered in ExAC. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Jan 05, 2024

This missense variant replaces aspartic acid with glycine at codon 345 of the DSP protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 12/250782 chromosomes 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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Benign	2.0	M;M
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.73
Sift	Benign	0.63	T;T
Sift4G	Benign	0.15	T;T
Polyphen		1.0	D;.
Vest4		0.70
MutPred		0.33		Gain of glycosylation at S344 (P = 0.0353);Gain of glycosylation at S344 (P = 0.0353);
MVP		0.90
MPC		0.95
ClinPred		0.45	T
GERP RS		5.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.66

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: rs753855393; hg19: chr6-7566704;