Genetic Variant DSP:c.-538G>C (chr6-7541378-G-C) – 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.47C>G 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 0.552 in 152,362 control chromosomes in the GnomAD database, including 24,417 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.55 ( 24381 hom., cov: 33)

Exomes 𝑓: 0.47 ( 36 hom. )

Consequence

DSP-AS1
NR_183327.1 non_coding_transcript_exon

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -3.79

Publications

0 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=-0.84).

BP6

Variant 6-7541378-G-C is Benign according to our data. Variant chr6-7541378-G-C is described in ClinVar as [Benign]. Clinvar id is 683473.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.736 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
DSP-AS1	NR_183327.1 link	n.47C>G	non_coding_transcript_exon_variant	Exon 1 of 2
DSP-AS1	NR_183328.1 link	n.119-325C>G	intron_variant	Intron 1 of 1
DSP-AS1	NR_183329.1 link	n.159-325C>G	intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
DSP	ENST00000418664.3 link	c.-538G>C	5_prime_UTR_variant	Exon 1 of 24	1	ENSP00000396591.2	P15924-2
DSP-AS1	ENST00000561592.3 link	n.50C>G	non_coding_transcript_exon_variant	Exon 1 of 1	6
DSP-AS1	ENST00000687028.3 link	n.102C>G	non_coding_transcript_exon_variant	Exon 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.552

AC:

83888

AN:

151976

Hom.:

24338

Cov.:

show subpopulations

Gnomad AFR

AF:

0.742

Gnomad AMI

AF:

0.470

Gnomad AMR

AF:

0.513

Gnomad ASJ

AF:

0.600

Gnomad EAS

AF:

0.300

Gnomad SAS

AF:

0.430

Gnomad FIN

AF:

0.446

Gnomad MID

AF:

0.541

Gnomad NFE

AF:

0.488

Gnomad OTH

AF:

0.532

GnomAD4 exome

AF:

0.467

AC:

129

AN:

276

Hom.:

Cov.:

AF XY:

0.403

AC XY:

AN XY:

176

show subpopulations

African (AFR)

AF:

0.700

AC:

AN:

American (AMR)

AF:

0.333

AC:

AN:

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AF:

0.500

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.436

AC:

AN:

220

Other (OTH)

AF:

0.556

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.552

AC:

83975

AN:

152086

Hom.:

24381

Cov.:

AF XY:

0.547

AC XY:

40670

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.743

AC:

30837

AN:

41520

American (AMR)

AF:

0.512

AC:

7831

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.600

AC:

2083

AN:

3472

East Asian (EAS)

AF:

0.300

AC:

1539

AN:

5136

South Asian (SAS)

AF:

0.430

AC:

2071

AN:

4816

European-Finnish (FIN)

AF:

0.446

AC:

4720

AN:

10588

Middle Eastern (MID)

AF:

0.538

AC:

157

AN:

292

European-Non Finnish (NFE)

AF:

0.488

AC:

33187

AN:

67946

Other (OTH)

AF:

0.530

AC:

1121

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1883

3765

5648

7530

9413

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.519

Hom.:

2713

Bravo

AF:

0.563

Asia WGS

AF:

0.386

AC:

1342

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jun 18, 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

-0.84

CADD

Benign

0.018

(source)

DANN

Benign

0.46

PhyloP100

-3.8

PromoterAI

0.16

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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6-7541378-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over