rs34884895

Variant names:

• chr6-7585562-C-A
• rs34884895
• NM_004415.4:c.8300C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7585562-C-A
• chr6-7585562-C-G
• chr6-7585562-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004415.4(DSP):​c.8300C>A​(p.Thr2767Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,614,108 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. T2767I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0064 (9 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (5 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:20
• Conservation: PhyloP100: 0.556
• Publications: 1 publications found

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):

• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, G2P, Genomics England PanelApp
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, Ambry Genetics, G2P, ClinGen
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet, G2P
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• dilated cardiomyopathy

  Inheritance: AD Classification: STRONG Submitted by: ClinGen
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, PanelApp Australia, Ambry Genetics
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056839883).
• BP6: Variant 6-7585562-C-A is Benign according to our data. Variant chr6-7585562-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0064 (974/152232) while in subpopulation AFR AF = 0.0227 (941/41534). AF 95% confidence interval is 0.0215. There are 9 homozygotes in GnomAd4. There are 425 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.8300C>A	p.Thr2767Asn	missense	Exon 24 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.6971C>A	p.Thr2324Asn	missense	Exon 24 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.6503C>A	p.Thr2168Asn	missense	Exon 24 of 24	NP_001008844.1	P15924-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.8300C>A	p.Thr2767Asn	missense	Exon 24 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.6503C>A	p.Thr2168Asn	missense	Exon 24 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.8174C>A	p.Thr2725Asn	missense	Exon 24 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.00641 AC: 975 AN: 152114 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.0227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

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: 0.0000147

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00171 AC: 429 AN: 251380 AF XY: 0.00116

Gnomad AFR exome AF: 0.0243

Gnomad AMR exome AF: 0.000839

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000642 AC: 939 AN: 1461876 Hom.: 5 Cov.: 37 AF XY: 0.000579 AC XY: 421 AN XY: 727238

African (AFR) AF: 0.0245 AC: 821 AN: 33480

American (AMR) AF: 0.000805 AC: 36 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53406

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1112010

Other (OTH) AF: 0.00113 AC: 68 AN: 60394

GnomAD4 genome AF: 0.00640 AC: 974 AN: 152232 Hom.: 9 Cov.: 32 AF XY: 0.00571 AC XY: 425 AN XY: 74432

African (AFR) AF: 0.0227 AC: 941 AN: 41534

American (AMR) AF: 0.00150 AC: 23 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68006

Other (OTH) AF: 0.00427 AC: 9 AN: 2108

Alfa AF: 0.00207 Hom.: 13

Bravo AF: 0.00681

ESP6500AA AF: 0.0227 AC: 100

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00212 AC: 257

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	Cardiomyopathy (3)
-	-	3	not provided (3)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Epidermolysis bullosa simplex due to plakophilin deficiency (1)
-	-	1	Hypertrophic cardiomyopathy;C1135191:Systolic heart failure (1)
-	-	1	Lethal acantholytic epidermolysis bullosa (1)
-	-	1	Woolly hair-skin fragility syndrome (1)
-	-	1	Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.47	T
Eigen	Benign	0.060
Eigen_PC	Benign	-0.014
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.97	D
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.56
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.21
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.90	P
Vest4		0.29
MVP		0.70
MPC		0.61
ClinPred		0.030	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.28
gMVP		0.44
Mutation Taster		=79/21	polymorphism

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

Other links and lift over

dbSNP: rs34884895; hg19: chr6-7585795;