rs28763971

Variant names:

• chr6-7585867-A-G
• rs28763971
• NM_004415.4:c.8605A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-7585867-A-G
• chr6-7585867-A-T
• chr6-7585867-A-C

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.8605A>G​(p.Ile2869Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000656 in 1,613,942 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. I2869T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (12 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: 0.913
• Publications: 5 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 (MetaRNN=0.0033507347).
• BP6: Variant 6-7585867-A-G is Benign according to our data. Variant chr6-7585867-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137173.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000939 (143/152268) while in subpopulation EAS AF = 0.0226 (117/5178). AF 95% confidence interval is 0.0193. There are 0 homozygotes in GnomAd4. There are 77 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 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.8605A>G	p.Ile2869Val	missense	Exon 24 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.7276A>G	p.Ile2426Val	missense	Exon 24 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.6808A>G	p.Ile2270Val	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.8605A>G	p.Ile2869Val	missense	Exon 24 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.6808A>G	p.Ile2270Val	missense	Exon 24 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.8479A>G	p.Ile2827Val	missense	Exon 24 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.000953 AC: 145 AN: 152150 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0229

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00217 AC: 541 AN: 249820 AF XY: 0.00191

Gnomad AFR exome AF: 0.000251

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000626 AC: 915 AN: 1461674 Hom.: 12 Cov.: 33 AF XY: 0.000571 AC XY: 415 AN XY: 727156

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.00119 AC: 53 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.0178 AC: 707 AN: 39700

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86222

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53272

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000522 AC: 58 AN: 1111996

Other (OTH) AF: 0.00131 AC: 79 AN: 60394

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152268 Hom.: 0 Cov.: 32 AF XY: 0.00103 AC XY: 77 AN XY: 74462

African (AFR) AF: 0.000193 AC: 8 AN: 41546

American (AMR) AF: 0.000523 AC: 8 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.0226 AC: 117 AN: 5178

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000266 Hom.: 0

Bravo AF: 0.00122

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00214 AC: 260

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Cardiomyopathy (2)
-	-	2	not provided (2)
-	-	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	Hypertrophic cardiomyopathy;C0023976:Long QT syndrome;C0042514:Ventricular tachycardia (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	0.067
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	14
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.081
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.91
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.59	T
Polyphen		0.055	B
Vest4		0.13
MVP		0.43
MPC		0.18
ClinPred		0.068	T
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.23
Mutation Taster		=96/4	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: rs28763971; hg19: chr6-7586100; COSMIC: COSV107426613; COSMIC: COSV107426613;