chr6-7556815-T-C

Variant names:

• chr6-7556815-T-C
• rs10484325
• NM_004415.4:c.273+995T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004415.4(DSP):​c.273+995T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 152,162 control chromosomes in the GnomAD database, including 2,217 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.16 (2217 hom., cov: 33)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.183
• Publications: 13 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):

• 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.273+995T>C		intron	N/A	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.273+995T>C		intron	N/A	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.273+995T>C		intron	N/A	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.273+995T>C		intron	N/A	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.273+995T>C		intron	N/A	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.147+995T>C		intron	N/A	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.162 AC: 24593 AN: 152044 Hom.: 2206 Cov.: 33

Gnomad AFR AF: 0.203

Gnomad AMI AF: 0.0945

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.00308

Gnomad SAS AF: 0.0520

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.165

Gnomad OTH AF: 0.164

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.162 AC: 24638 AN: 152162 Hom.: 2217 Cov.: 33 AF XY: 0.156 AC XY: 11576 AN XY: 74374

African (AFR) AF: 0.203 AC: 8435 AN: 41494

American (AMR) AF: 0.116 AC: 1771 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 688 AN: 3468

East Asian (EAS) AF: 0.00308 AC: 16 AN: 5190

South Asian (SAS) AF: 0.0526 AC: 254 AN: 4826

European-Finnish (FIN) AF: 0.167 AC: 1765 AN: 10580

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.165 AC: 11244 AN: 68006

Other (OTH) AF: 0.162 AC: 343 AN: 2116

Alfa AF: 0.162 Hom.: 3749

Bravo AF: 0.160

Asia WGS AF: 0.0460 AC: 159 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.5
DANN	Benign	0.52
PhyloP100		0.18
Mutation Taster		=99/1	polymorphism (auto)

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: rs10484325; hg19: chr6-7557048;