dbSNP rs368802003: DSP:p.Asn4Lys (chr6-7541927-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004415.4(DSP):c.12C>G(p.Asn4Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,608,092 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N4S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0023 ( 6 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 29 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.129

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049898326).

BP6

Variant 6-7541927-C-G is Benign according to our data. Variant chr6-7541927-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44858.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00231 (348/150548) while in subpopulation AMR AF = 0.0219 (332/15146). AF 95% confidence interval is 0.02. There are 6 homozygotes in GnomAd4. There are 219 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 6 AD,AR gene

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.12C>G	p.Asn4Lys	missense	Exon 1 of 24	NP_004406.2	P15924-1
DSP	NM_001319034.2		c.12C>G	p.Asn4Lys	missense	Exon 1 of 24	NP_001305963.1	P15924-3
DSP	NM_001008844.3		c.12C>G	p.Asn4Lys	missense	Exon 1 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.12C>G	p.Asn4Lys	missense	Exon 1 of 24	ENSP00000369129.3	P15924-1
DSP	ENST00000418664.3	TSL:1	c.12C>G	p.Asn4Lys	missense	Exon 1 of 24	ENSP00000396591.2	P15924-2
DSP	ENST00000710359.2		c.12C>G	p.Asn4Lys	missense	Exon 1 of 24	ENSP00000518230.1	P15924-3

Frequencies

GnomAD3 genomes

AF:

0.00231

AC:

347

AN:

150430

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0219

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:

0.00290

GnomAD2 exomes

AF:

0.00516

AC:

1199

AN:

232464

AF XY:

0.00358

show subpopulations

Gnomad AFR exome

AF:

0.000435

Gnomad AMR exome

AF:

0.0347

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00211

GnomAD4 exome

AF:

0.00102

AC:

1484

AN:

1457544

Hom.:

Cov.:

AF XY:

0.000832

AC XY:

603

AN XY:

724808

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33408

American (AMR)

AF:

0.0318

AC:

1414

AN:

44428

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26048

East Asian (EAS)

AF:

0.00

AC:

AN:

39600

South Asian (SAS)

AF:

0.000210

AC:

AN:

85706

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51470

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1110976

Other (OTH)

AF:

0.000598

AC:

AN:

60182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

147

220

294

367

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

<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:

0.00231

AC:

348

AN:

150548

Hom.:

Cov.:

AF XY:

0.00298

AC XY:

219

AN XY:

73576

show subpopulations

African (AFR)

AF:

0.000245

AC:

AN:

40848

American (AMR)

AF:

0.0219

AC:

332

AN:

15146

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5040

South Asian (SAS)

AF:

0.00

AC:

AN:

4736

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67488

Other (OTH)

AF:

0.00287

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000989

Hom.:

Bravo

AF:

0.00401

ExAC

AF:

0.00364

AC:

438

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Cardiomyopathy (2)

Arrhythmogenic right ventricular dysplasia 8 (1)

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

Cardiovascular phenotype (1)

Lethal acantholytic epidermolysis bullosa (1)

not provided (1)

Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.096

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.55

PhyloP100

0.13

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

-0.41

REVEL

Benign

0.11

Sift

Uncertain

0.0090

Sift4G

Pathogenic

0.0

Polyphen

0.89

Vest4

0.32

MutPred

0.24

Gain of methylation at N4 (P = 0.002)

MVP

0.52

MPC

0.31

ClinPred

0.031

GERP RS

3.0

PromoterAI

0.0068

Neutral

(source)

Varity_R

0.20

gMVP

0.65

Mutation Taster

=96/4

polymorphism

(source)

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

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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