rs146737031

Variant names:

• chr6-7567794-C-T
• rs146737031
• NM_004415.4:c.1154C>T
• DSP p.Ala385Val

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_004415.4(DSP):​c.1154C>T​(p.Ala385Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000551 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A385A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.06
• Publications: 2 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: Ambry Genetics, G2P, Genomics England PanelApp
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), ClinGen, Genomics England PanelApp, G2P, Orphanet
• 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: Ambry Genetics, Genomics England PanelApp, G2P, Orphanet
• cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis

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

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

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.20913607).
• BP6: Variant 6-7567794-C-T is Benign according to our data. Variant chr6-7567794-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 246658.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 = 0.000263 (40/152170) while in subpopulation AFR AF = 0.000963 (40/41520). AF 95% confidence interval is 0.000727. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.1154C>T	p.Ala385Val	missense	Exon 10 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.1154C>T	p.Ala385Val	missense	Exon 10 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.1154C>T	p.Ala385Val	missense	Exon 10 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.1154C>T	p.Ala385Val	missense	Exon 10 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.1154C>T	p.Ala385Val	missense	Exon 10 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000713904.1		c.1028C>T	p.Ala343Val	missense	Exon 10 of 24	ENSP00000519203.1	A0AAQ5BH40

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152054 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000103 AC: 26 AN: 251226 AF XY: 0.0000516

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000335 AC: 49 AN: 1461674 Hom.: 0 Cov.: 34 AF XY: 0.0000206 AC XY: 15 AN XY: 727144

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

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

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111882

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74388

African (AFR) AF: 0.000963 AC: 40 AN: 41520

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10578

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67998

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000374 Hom.: 0

Bravo AF: 0.000287

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	26
DANN	Benign	0.86
DEOGEN2	Benign	0.35	T
Eigen	Benign	0.00060
Eigen_PC	Benign	0.051
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.029	D
MutationAssessor	Benign	0.41	N
PhyloP100		4.1
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.54	N
REVEL	Uncertain	0.60
Sift	Benign	0.39	T
Sift4G	Benign	0.78	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.20
gMVP		0.55
Mutation Taster		=20/80	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs146737031;

hg19: chr6-7568027;