rs397516924

Positions:

chr6-7576954-T-TA

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP6

The NM_004415.4(DSP):c.2794-4dup variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000415 in 1,612,572 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

DSP
NM_004415.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -1.36

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 Likely_benign. Variant got -1 ACMG points.

BP6

Variant 6-7576954-T-TA is Benign according to our data. Variant chr6-7576954-T-TA is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44882.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
DSP	NM_004415.4 linkuse as main transcript	c.2794-4dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	ENST00000379802.8
DSP	NM_001008844.3 linkuse as main transcript	c.2794-4dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
DSP	NM_001319034.2 linkuse as main transcript	c.2794-4dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.2794-4dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1	NM_004415.4	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.2794-4dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant	1		A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.2794-4dup	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			A2

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000519

AC:

AN:

250666

Hom.:

AF XY:

0.0000369

AC XY:

AN XY:

135472

show subpopulations

Gnomad AFR exome

AF:

0.000801

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000247

AC:

AN:

1460204

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726282

show subpopulations

Gnomad4 AFR exome

AF:

0.000927

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000829

GnomAD4 genome

AF:

0.000203

AC:

AN:

152368

Hom.:

Cov.:

AF XY:

0.000242

AC XY:

AN XY:

74516

show subpopulations

Gnomad4 AFR

AF:

0.000745

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.000276

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 28, 2015	Variant classified as Uncertain Significance - Favor Benign. The c.2794-4_2794-3 insA variant in DSP has been previously reported by our laboratory in 2 African American individuals, 1 with DCM and 1 with an unspecified cardiomyopathy. It h as also been identified in 0.1% (12/10132) of African chromosomes by the Exome A ggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs397516924). This variant is located in the 3' splice region. Computational tools do not sug gest an impact to splicing. However, this information is not predictive enough t o rule out pathogenicity. In summary, while the clinical significance of the c.2 794-4_2794-3insA variant is uncertain, its frequency suggests that it is more li kely to be benign. -

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 11, 2024

- -

Cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Apr 15, 2019

- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 28, 2022

See Variant Classification Assertion Criteria. -

Cardiovascular phenotype

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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