Genetic Variant NM_004415.4:c.423-16_423-15insC (chr6-7559210-G-GC) – ACMG Classification: Benign (-16 pts)

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBA1

The NM_004415.4(DSP):c.423-16_423-15insC variant causes a 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 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 0.261

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4 link	c.423-16_423-15insC	intron_variant	Intron 3 of 23	ENST00000379802.8	NP_004406.2	P15924-1B4DKX6
DSP	NM_001319034.2 link	c.423-16_423-15insC	intron_variant	Intron 3 of 23		NP_001305963.1	P15924-3B4DKX6
DSP	NM_001008844.3 link	c.423-16_423-15insC	intron_variant	Intron 3 of 23		NP_001008844.1	P15924-2B4DKX6Q4LE79
DSP	NM_001406591.1 link	c.423-16_423-15insC	intron_variant	Intron 3 of 10		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8 link	c.423-16_423-15insC		intron_variant	Intron 3 of 23	1	NM_004415.4	ENSP00000369129.3		P15924-1

Frequencies

GnomAD3 genomes

AF:

0.0280

AC:

4254

AN:

152090

Hom.:

180

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.00288

AC XY:

2093

AN XY:

726960

show subpopulations

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.:

AF XY:

0.0277

AC XY:

2060

AN XY:

74422

show subpopulations

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.:

Bravo

AF:

0.0319

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

May 24, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 22, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

May 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiomyopathy

Benign:1

Sep 23, 2022

Cohesion Phenomics

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over