NM_004415.4:c.273+10C>T

Variant names:

• chr6-7555830-C-T
• rs56148603
• NM_004415.4:c.273+10C>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.273+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0329 in 1,612,588 control chromosomes in the GnomAD database, including 1,038 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (61 hom., cov: 33)
  • Exomes 𝑓: 0.034 (977 hom.)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.558
• 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):

• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 6-7555830-C-T is Benign according to our data. Variant chr6-7555830-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 44879.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.024 (3664/152350) while in subpopulation NFE AF = 0.0376 (2557/68034). AF 95% confidence interval is 0.0364. There are 61 homozygotes in GnomAd4. There are 1647 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 61 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.273+10C>T		intron	N/A	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.273+10C>T		intron	N/A	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.273+10C>T		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+10C>T		intron	N/A	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.273+10C>T		intron	N/A	ENSP00000396591.2	P15924-2
	DSP	ENST00000683682.2		c.283C>T	p.Pro95Ser	missense	Exon 2 of 2	ENSP00000508162.2	A0A804HL18

Frequencies

GnomAD3 genomes AF: 0.0241 AC: 3665 AN: 152232 Hom.: 61 Cov.: 33

Gnomad AFR AF: 0.00644

Gnomad AMI AF: 0.0669

Gnomad AMR AF: 0.0306

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.0139

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0376

Gnomad OTH AF: 0.0306

GnomAD2 exomes AF: 0.0235 AC: 5851 AN: 249090 AF XY: 0.0237

Gnomad AFR exome AF: 0.00566

Gnomad AMR exome AF: 0.0210

Gnomad ASJ exome AF: 0.0148

Gnomad EAS exome AF: 0.0000548

Gnomad FIN exome AF: 0.0128

Gnomad NFE exome AF: 0.0371

Gnomad OTH exome AF: 0.0310

GnomAD4 exome AF: 0.0338 AC: 49415 AN: 1460238 Hom.: 977 Cov.: 31 AF XY: 0.0333 AC XY: 24190 AN XY: 726392

African (AFR) AF: 0.00548 AC: 183 AN: 33420

American (AMR) AF: 0.0223 AC: 997 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 383 AN: 26126

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39622

South Asian (SAS) AF: 0.00875 AC: 754 AN: 86126

European-Finnish (FIN) AF: 0.0144 AC: 765 AN: 52946

Middle Eastern (MID) AF: 0.0194 AC: 112 AN: 5766

European-Non Finnish (NFE) AF: 0.0400 AC: 44488 AN: 1111254

Other (OTH) AF: 0.0287 AC: 1730 AN: 60330

GnomAD4 genome AF: 0.0240 AC: 3664 AN: 152350 Hom.: 61 Cov.: 33 AF XY: 0.0221 AC XY: 1647 AN XY: 74496

African (AFR) AF: 0.00642 AC: 267 AN: 41588

American (AMR) AF: 0.0305 AC: 467 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.00850 AC: 41 AN: 4826

European-Finnish (FIN) AF: 0.0139 AC: 148 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0376 AC: 2557 AN: 68034

Other (OTH) AF: 0.0302 AC: 64 AN: 2116

Alfa AF: 0.0270 Hom.: 35

Bravo AF: 0.0249

Asia WGS AF: 0.00318 AC: 12 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	8	not specified (8)
-	-	2	not provided (2)
-	-	1	Arrhythmogenic right ventricular dysplasia 8 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiomyopathy (1)
-	-	1	Lethal acantholytic epidermolysis bullosa (1)
-	-	1	Woolly hair-skin fragility syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	6.5
DANN	Benign	0.69
PhyloP100		0.56
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs56148603; hg19: chr6-7556063;