6-7558085-T-C

Variant names:

• chr6-7558085-T-C
• rs10484326
• NM_004415.4:c.274-31T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004415.4(DSP):​c.274-31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.224 in 1,613,050 control chromosomes in the GnomAD database, including 42,278 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (3519 hom., cov: 33)
  • Exomes 𝑓: 0.23 (38759 hom.)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0860
• Publications: 17 publications found

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 Gene-Disease associations (from GenCC):

• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, ClinGen, Orphanet, Ambry Genetics
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• familial isolated dilated cardiomyopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• striate palmoplantar keratoderma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• severe dermatitis-multiple allergies-metabolic wasting syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• hypertrophic cardiomyopathy

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-7558085-T-C is Benign according to our data. Variant chr6-7558085-T-C is described in ClinVar as Benign. ClinVar VariationId is 137167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.274-31T>C		intron_variant	Intron 2 of 23	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.274-31T>C		intron_variant	Intron 2 of 23		NP_001305963.1
DSP	NM_001008844.3	c.274-31T>C		intron_variant	Intron 2 of 23		NP_001008844.1
DSP	NM_001406591.1	c.274-31T>C		intron_variant	Intron 2 of 10		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.274-31T>C		intron_variant	Intron 2 of 23	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31404 AN: 152106 Hom.: 3516 Cov.: 33

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.195

Gnomad AMR AF: 0.176

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.0494

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.267

Gnomad MID AF: 0.307

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.210

GnomAD2 exomes AF: 0.197 AC: 49393 AN: 251312 AF XY: 0.200

Gnomad AFR exome AF: 0.169

Gnomad AMR exome AF: 0.128

Gnomad ASJ exome AF: 0.300

Gnomad EAS exome AF: 0.0440

Gnomad FIN exome AF: 0.257

Gnomad NFE exome AF: 0.236

Gnomad OTH exome AF: 0.215

GnomAD4 exome AF: 0.225 AC: 329155 AN: 1460826 Hom.: 38759 Cov.: 33 AF XY: 0.224 AC XY: 162683 AN XY: 726820

African (AFR) AF: 0.165 AC: 5521 AN: 33444

American (AMR) AF: 0.136 AC: 6104 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.298 AC: 7791 AN: 26132

East Asian (EAS) AF: 0.0415 AC: 1649 AN: 39696

South Asian (SAS) AF: 0.158 AC: 13585 AN: 86240

European-Finnish (FIN) AF: 0.255 AC: 13633 AN: 53408

Middle Eastern (MID) AF: 0.269 AC: 1550 AN: 5768

European-Non Finnish (NFE) AF: 0.239 AC: 265543 AN: 1111070

Other (OTH) AF: 0.228 AC: 13779 AN: 60348

GnomAD4 genome AF: 0.206 AC: 31404 AN: 152224 Hom.: 3519 Cov.: 33 AF XY: 0.206 AC XY: 15305 AN XY: 74426

African (AFR) AF: 0.167 AC: 6957 AN: 41550

American (AMR) AF: 0.176 AC: 2689 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 1063 AN: 3470

East Asian (EAS) AF: 0.0490 AC: 254 AN: 5188

South Asian (SAS) AF: 0.158 AC: 761 AN: 4826

European-Finnish (FIN) AF: 0.267 AC: 2830 AN: 10588

Middle Eastern (MID) AF: 0.296 AC: 87 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16148 AN: 67986

Other (OTH) AF: 0.207 AC: 438 AN: 2112

Alfa AF: 0.226 Hom.: 7754

Bravo AF: 0.199

Asia WGS AF: 0.121 AC: 421 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 20, 2013

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.63
DANN	Benign	0.65
PhyloP100		0.086
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs10484326; hg19: chr6-7558318; COSMIC: COSV65793233; COSMIC: COSV65793233;