rs10484326

chr6-7558085-T-C

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id is 137167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7558085-T-C is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
DSP	NM_004415.4	c.274-31T>C		intron_variant		ENST00000379802.8
DSP	NM_001008844.3	c.274-31T>C		intron_variant
DSP	NM_001319034.2	c.274-31T>C		intron_variant
DSP	NM_001406591.1	c.274-31T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.274-31T>C		intron_variant		1	NM_004415.4	P2
DSP	ENST00000418664.2	c.274-31T>C		intron_variant		1		A2
DSP	ENST00000710359.1	c.274-31T>C		intron_variant				A2
DSP	ENST00000683563.1	n.166-31T>C		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes AF: 0.197 AC: 49393 AN: 251312 Hom.: 5408 AF XY: 0.200 AC XY: 27131 AN XY: 135850

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 SAS exome AF: 0.153

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

Gnomad4 AFR exome AF: 0.165

Gnomad4 AMR exome AF: 0.136

Gnomad4 ASJ exome AF: 0.298

Gnomad4 EAS exome AF: 0.0415

Gnomad4 SAS exome AF: 0.158

Gnomad4 FIN exome AF: 0.255

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.228

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

Gnomad4 AFR AF: 0.167

Gnomad4 AMR AF: 0.176

Gnomad4 ASJ AF: 0.306

Gnomad4 EAS AF: 0.0490

Gnomad4 SAS AF: 0.158

Gnomad4 FIN AF: 0.267

Gnomad4 NFE AF: 0.238

Gnomad4 OTH AF: 0.207

Alfa AF: 0.231 Hom.: 5979

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

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.63
Dann	Benign	0.65

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