dbSNP rs1016835: DSP:p.Arg877Arg (chr6-7576294-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004415.4(DSP):c.2631G>A(p.Arg877Arg) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 1,612,944 control chromosomes in the GnomAD database, including 495,137 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R877R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.75 ( 43138 hom., cov: 32)

Exomes 𝑓: 0.79 ( 451999 hom. )

Consequence

DSP
NM_004415.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0001223

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:20

Conservation

PhyloP100: 0.269

Publications

26 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 Gene-Disease associations (from GenCC):

keratosis palmoplantaris striata 2
Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, G2P
arrhythmogenic cardiomyopathy with wooly hair and keratoderma
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen
arrhythmogenic right ventricular dysplasia 8
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
skin fragility-woolly hair-palmoplantar keratoderma syndrome
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, G2P, Ambry Genetics, Orphanet
cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
dilated cardiomyopathy
Inheritance: AD Classification: STRONG Submitted by: ClinGen
lethal acantholytic epidermolysis bullosa
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet
familial isolated dilated cardiomyopathy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
striate palmoplantar keratoderma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
severe dermatitis-multiple allergies-metabolic wasting syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
hypertrophic cardiomyopathy
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

DSP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 6-7576294-G-A is Benign according to our data. Variant chr6-7576294-G-A is described in ClinVar as Benign. ClinVar VariationId is 44877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.269 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004415.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSP	NM_004415.4	MANE Select	c.2631G>A	p.Arg877Arg	splice_region synonymous	Exon 19 of 24	NP_004406.2	P15924-1
DSP	NM_001319034.2		c.2631G>A	p.Arg877Arg	splice_region synonymous	Exon 19 of 24	NP_001305963.1	P15924-3
DSP	NM_001008844.3		c.2631G>A	p.Arg877Arg	splice_region synonymous	Exon 19 of 24	NP_001008844.1	P15924-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DSP	ENST00000379802.8	TSL:1 MANE Select	c.2631G>A	p.Arg877Arg	splice_region synonymous	Exon 19 of 24	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.3	TSL:1	c.2631G>A	p.Arg877Arg	splice_region synonymous	Exon 19 of 24	ENSP00000396591.2	P15924-2
DSP	ENST00000713904.1		c.2505G>A	p.Arg835Arg	splice_region synonymous	Exon 19 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes

AF:

0.749

AC:

113851

AN:

151938

Hom.:

43118

Cov.:

show subpopulations

Gnomad AFR

AF:

0.645

Gnomad AMI

AF:

0.863

Gnomad AMR

AF:

0.793

Gnomad ASJ

AF:

0.825

Gnomad EAS

AF:

0.799

Gnomad SAS

AF:

0.747

Gnomad FIN

AF:

0.716

Gnomad MID

AF:

0.816

Gnomad NFE

AF:

0.798

Gnomad OTH

AF:

0.776

GnomAD2 exomes

AF:

0.775

AC:

194456

AN:

251060

AF XY:

0.777

show subpopulations

Gnomad AFR exome

AF:

0.642

Gnomad AMR exome

AF:

0.785

Gnomad ASJ exome

AF:

0.817

Gnomad EAS exome

AF:

0.803

Gnomad FIN exome

AF:

0.718

Gnomad NFE exome

AF:

0.801

Gnomad OTH exome

AF:

0.786

GnomAD4 exome

AF:

0.786

AC:

1147720

AN:

1460886

Hom.:

451999

Cov.:

AF XY:

0.786

AC XY:

570968

AN XY:

726784

show subpopulations

African (AFR)

AF:

0.631

AC:

21124

AN:

33454

American (AMR)

AF:

0.789

AC:

35283

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.815

AC:

21281

AN:

26124

East Asian (EAS)

AF:

0.812

AC:

32221

AN:

39670

South Asian (SAS)

AF:

0.745

AC:

64195

AN:

86220

European-Finnish (FIN)

AF:

0.719

AC:

38396

AN:

53390

Middle Eastern (MID)

AF:

0.796

AC:

4584

AN:

5762

European-Non Finnish (NFE)

AF:

0.795

AC:

883370

AN:

1111206

Other (OTH)

AF:

0.783

AC:

47266

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

11478

22955

34433

45910

57388

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20690

41380

62070

82760

103450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.749

AC:

113923

AN:

152058

Hom.:

43138

Cov.:

AF XY:

0.748

AC XY:

55609

AN XY:

74324

show subpopulations

African (AFR)

AF:

0.645

AC:

26749

AN:

41448

American (AMR)

AF:

0.793

AC:

12119

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.825

AC:

2862

AN:

3470

East Asian (EAS)

AF:

0.798

AC:

4122

AN:

5164

South Asian (SAS)

AF:

0.747

AC:

3599

AN:

4816

European-Finnish (FIN)

AF:

0.716

AC:

7572

AN:

10576

Middle Eastern (MID)

AF:

0.830

AC:

244

AN:

294

European-Non Finnish (NFE)

AF:

0.798

AC:

54239

AN:

67984

Other (OTH)

AF:

0.771

AC:

1632

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1472

2944

4417

5889

7361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

848

1696

2544

3392

4240

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.788

Hom.:

211957

Bravo

AF:

0.751

Asia WGS

AF:

0.727

AC:

2526

AN:

3478

EpiCase

AF:

0.818

EpiControl

AF:

0.808

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (7)

Cardiomyopathy (2)

Lethal acantholytic epidermolysis bullosa (2)

Woolly hair-skin fragility syndrome (2)

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)

Arrhythmogenic right ventricular dysplasia 8 (1)

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

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (1)

Cardiovascular phenotype (1)

Keratosis palmoplantaris striata 2 (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.57

CADD

Benign

5.7

(source)

DANN

Benign

0.70

PhyloP100

0.27

Mutation Taster

=66/34

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00012

dbscSNV1_RF

Benign

0.030

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over