6-7565494-A-T

Variant names:

• chr6-7565494-A-T
• rs17604693
• NM_004415.4:c.913A>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004415.4(DSP):​c.913A>T​(p.Ile305Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0366 in 1,613,890 control chromosomes in the GnomAD database, including 1,250 homozygotes. In-silico tool predicts 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. I305V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.027 (93 hom., cov: 31)
  • Exomes 𝑓: 0.038 (1157 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:23
• Conservation: PhyloP100: 9.20
• Publications: 21 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 21 uncertain in NM_004415.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029249191).
• BP6: Variant 6-7565494-A-T is Benign according to our data. Variant chr6-7565494-A-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 36026.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 = 0.0269 (4099/152148) while in subpopulation NFE AF = 0.0408 (2771/67978). AF 95% confidence interval is 0.0395. There are 93 homozygotes in GnomAd4. There are 1921 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 93 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.913A>T	p.Ile305Phe	missense	Exon 7 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.913A>T	p.Ile305Phe	missense	Exon 7 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.913A>T	p.Ile305Phe	missense	Exon 7 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.913A>T	p.Ile305Phe	missense	Exon 7 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.913A>T	p.Ile305Phe	missense	Exon 7 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.787A>T	p.Ile263Phe	missense	Exon 7 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.0270 AC: 4098 AN: 152030 Hom.: 94 Cov.: 31

Gnomad AFR AF: 0.00604

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.0190

Gnomad ASJ AF: 0.0467

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0384

Gnomad FIN AF: 0.0212

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0408

Gnomad OTH AF: 0.0210

GnomAD2 exomes AF: 0.0296 AC: 7436 AN: 251262 AF XY: 0.0315

Gnomad AFR exome AF: 0.00652

Gnomad AMR exome AF: 0.0153

Gnomad ASJ exome AF: 0.0447

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.0245

Gnomad NFE exome AF: 0.0396

Gnomad OTH exome AF: 0.0342

GnomAD4 exome AF: 0.0376 AC: 54918 AN: 1461742 Hom.: 1157 Cov.: 32 AF XY: 0.0378 AC XY: 27494 AN XY: 727180

African (AFR) AF: 0.00568 AC: 190 AN: 33476

American (AMR) AF: 0.0157 AC: 702 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0453 AC: 1183 AN: 26132

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.0373 AC: 3214 AN: 86258

European-Finnish (FIN) AF: 0.0248 AC: 1324 AN: 53410

Middle Eastern (MID) AF: 0.0304 AC: 175 AN: 5764

European-Non Finnish (NFE) AF: 0.0414 AC: 46062 AN: 1111894

Other (OTH) AF: 0.0341 AC: 2062 AN: 60388

GnomAD4 genome AF: 0.0269 AC: 4099 AN: 152148 Hom.: 93 Cov.: 31 AF XY: 0.0258 AC XY: 1921 AN XY: 74386

African (AFR) AF: 0.00602 AC: 250 AN: 41514

American (AMR) AF: 0.0190 AC: 290 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0467 AC: 162 AN: 3470

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5176

South Asian (SAS) AF: 0.0393 AC: 189 AN: 4810

European-Finnish (FIN) AF: 0.0212 AC: 225 AN: 10600

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0408 AC: 2771 AN: 67978

Other (OTH) AF: 0.0203 AC: 43 AN: 2116

Alfa AF: 0.0354 Hom.: 99

Bravo AF: 0.0256

TwinsUK AF: 0.0445 AC: 165

ALSPAC AF: 0.0464 AC: 179

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0419 AC: 360

ExAC AF: 0.0299 AC: 3632

Asia WGS AF: 0.0100 AC: 36 AN: 3478

EpiCase AF: 0.0417

EpiControl AF: 0.0411

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	10	not specified (10)
-	-	4	Cardiomyopathy (4)
-	-	3	not provided (3)
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8 (1)
-	-	1	Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma (1)
-	-	1	Cardiovascular phenotype (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
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.82	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
MetaRNN	Benign	0.0029	T
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.59
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.031	D
Polyphen		1.0	D
Vest4		0.29
MPC		1.0
ClinPred		0.027	T
GERP RS		5.5
Varity_R		0.40
gMVP		0.72
Mutation Taster		=81/19	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: rs17604693; hg19: chr6-7565727; COSMIC: COSV65792675;