rs113028223

chr6-7559210-G-GC

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004415.4(DSP):c.423-16_423-15insC variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,613,606 control chromosomes in the GnomAD database, including 391 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (190 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (201 hom.)
• Consequence: DSP NM_004415.4 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.261

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 -16 ACMG points.

• BP6: Variant 6-7559210-G-GC is Benign according to our data. Variant chr6-7559210-G-GC is described in ClinVar as [Likely_benign]. Clinvar id is 44902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.423-16_423-15insC		splice_polypyrimidine_tract_variant, intron_variant		ENST00000379802.8
DSP	NM_001008844.3	c.423-16_423-15insC		splice_polypyrimidine_tract_variant, intron_variant
DSP	NM_001319034.2	c.423-16_423-15insC		splice_polypyrimidine_tract_variant, intron_variant
DSP	NM_001406591.1	c.423-16_423-15insC		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.423-16_423-15insC		splice_polypyrimidine_tract_variant, intron_variant		1	NM_004415.4	P2
DSP	ENST00000418664.2	c.423-16_423-15insC		splice_polypyrimidine_tract_variant, intron_variant		1		A2
DSP	ENST00000710359.1	c.423-16_423-15insC		splice_polypyrimidine_tract_variant, intron_variant				A2
DSP	ENST00000683563.1	n.315-16_315-15insC		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.0280 AC: 4254 AN: 152090 Hom.: 180 Cov.: 32

Gnomad AFR AF: 0.0967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0104

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000221

Gnomad OTH AF: 0.0206

GnomAD3 exomes AF: 0.00800 AC: 1994 AN: 249314 Hom.: 103 AF XY: 0.00635 AC XY: 858 AN XY: 135108

Gnomad AFR exome AF: 0.102

Gnomad AMR exome AF: 0.00506

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00487

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000214

Gnomad OTH exome AF: 0.00328

GnomAD4 exome AF: 0.00315 AC: 4607 AN: 1461398 Hom.: 201 Cov.: 31 AF XY: 0.00288 AC XY: 2093 AN XY: 726960

Gnomad4 AFR exome AF: 0.101

Gnomad4 AMR exome AF: 0.00550

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00486

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000109

Gnomad4 OTH exome AF: 0.00683

GnomAD4 genome AF: 0.0282 AC: 4291 AN: 152208 Hom.: 190 Cov.: 32 AF XY: 0.0277 AC XY: 2060 AN XY: 74422

Gnomad4 AFR AF: 0.0973

Gnomad4 AMR AF: 0.0104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00684

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000221

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0116 Hom.: 12

Bravo AF: 0.0319

Asia WGS AF: 0.0120 AC: 41 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 24, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2018	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 22, 2016	Variant summary: The DSP c.423-16_423-15insC variant involves the insetion of an intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. This variant was found in 1200/120544 control chromosomes (58 homozygotes), predominantly observed in the African subpopulation at a frequency of 0.1054381 (1047/9930). This frequency is about 4217 times the estimated maximal expected allele frequency of a pathogenic DSP variant (0.000025), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. Taken together, this variant is classified as benign. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Cardiomyopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

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: rs113028223; hg19: chr6-7559443;