rs368778031

chr6-7569267-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM1 BP4_Moderate BP6

The NM_004415.4(DSP):c.1501G>A(p.Val501Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V501A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000016 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.64

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 -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 11 uncertain in NM_004415.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.18126428).
• BP6: Variant 6-7569267-G-A is Benign according to our data. Variant chr6-7569267-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178025.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.1501G>A	p.Val501Ile	missense_variant	12/24	ENST00000379802.8
DSP	NM_001319034.2	c.1501G>A	p.Val501Ile	missense_variant	12/24
DSP	NM_001008844.3	c.1501G>A	p.Val501Ile	missense_variant	12/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.1501G>A	p.Val501Ile	missense_variant	12/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.1501G>A	p.Val501Ile	missense_variant	12/24	1		A2
DSP	ENST00000710359.1	c.1501G>A	p.Val501Ile	missense_variant	12/24			A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251454 Hom.: 0 AF XY: 0.0000441 AC XY: 6 AN XY: 135906

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000157 AC: 23 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000576 AC: 7

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 08, 2014

The Val501Ile variant in DSP has not been previously reported in individuals wit h cardiomyopathy, but has been identified in 1/8600 of European American chromos omes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/). Computational prediction tools and conservation analysis do not provide strong s upport for or against an impact to the protein. In summary, the clinical signifi cance of the Val501Ile variant is uncertain. -

Cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Sep 01, 2023

This missense variant replaces valine with isoleucine at codon 501 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 been reported in an individual suspected of having hypertrophic cardiomyopathy (PMID: 30847666). This variant has also been identified in 8/251454 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 13, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.34
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	0.064
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.97	L;L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.020	N;N
REVEL	Benign	0.16
Sift	Benign	0.59	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.25	B;.
Vest4		0.48
MVP		0.60
MPC		0.39
ClinPred		0.11	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs368778031; hg19: chr6-7569500; COSMIC: COSV65792409; COSMIC: COSV65792409;