Genetic Variant DSP:c.-566G>A (chr6-7541350-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NR_183327.1(DSP-AS1):n.75C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0473 in 152,454 control chromosomes in the GnomAD database, including 551 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.047 ( 550 hom., cov: 34)

Exomes 𝑓: 0.026 ( 1 hom. )

Consequence

DSP-AS1
NR_183327.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.191

Publications

1 publications found

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:

DSP-AS1 (HGNC:56039): (DSP antisense RNA 1)

DSP-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 6-7541350-G-A is Benign according to our data. Variant chr6-7541350-G-A is described in ClinVar as [Benign]. Clinvar id is 669423.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
DSP-AS1	NR_183327.1 link	n.75C>T	non_coding_transcript_exon_variant	Exon 1 of 2
DSP-AS1	NR_183328.1 link	n.119-297C>T	intron_variant	Intron 1 of 1
DSP-AS1	NR_183329.1 link	n.159-297C>T	intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
DSP	ENST00000418664.3 link	c.-566G>A	5_prime_UTR_variant	Exon 1 of 24	1	ENSP00000396591.2	P15924-2
DSP-AS1	ENST00000561592.3 link	n.78C>T	non_coding_transcript_exon_variant	Exon 1 of 1	6
DSP-AS1	ENST00000687028.3 link	n.130C>T	non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.0472

AC:

7176

AN:

152184

Hom.:

548

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0220

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00404

Gnomad SAS

AF:

0.00745

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000529

Gnomad OTH

AF:

0.0401

GnomAD4 exome

AF:

0.0256

AC:

AN:

156

Hom.:

Cov.:

AF XY:

0.0364

AC XY:

AN XY:

110

show subpopulations

African (AFR)

AF:

0.300

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

112

Other (OTH)

AF:

0.0625

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0473

AC:

7210

AN:

152298

Hom.:

550

Cov.:

AF XY:

0.0450

AC XY:

3349

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.161

AC:

6690

AN:

41564

American (AMR)

AF:

0.0220

AC:

337

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00405

AC:

AN:

5180

South Asian (SAS)

AF:

0.00746

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0137

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000529

AC:

AN:

68010

Other (OTH)

AF:

0.0397

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

325

649

974

1298

1623

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0361

Hom.:

Bravo

AF:

0.0551

Asia WGS

AF:

0.0150

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

6.0

(source)

DANN

Benign

0.83

PhyloP100

-0.19

PromoterAI

-0.023

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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chr6-7541350-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over