ENST00000418664.3:c.-281C>T

Variant names:

• chr6-7541635-C-T
• rs547069600
• ENST00000418664.3:c.-281C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000418664.3(DSP):​c.-281C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000515 in 461,774 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00022 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00066 (2 hom.)
• Consequence: DSP ENST00000418664.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:4
• Conservation: PhyloP100: 0.584
• 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-AS1 (HGNC:56039): (DSP antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 6-7541635-C-T is Benign according to our data. Variant chr6-7541635-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 369568.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000217 (33/152314) while in subpopulation EAS AF = 0.0062 (32/5162). AF 95% confidence interval is 0.00451. There are 1 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000418664.3. 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-AS1	NR_183328.1		n.119-582G>A		intron	N/A
	DSP-AS1	NR_183329.1		n.159-582G>A		intron	N/A
	DSP-AS1	NR_183330.1		n.626-582G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000418664.3	TSL:1	c.-281C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000418664.3	TSL:1	c.-281C>T		5_prime_UTR	Exon 1 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000710359.2		c.-281C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000518230.1	P15924-3

Frequencies

GnomAD3 genomes AF: 0.000217 AC: 33 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00618

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000662 AC: 205 AN: 309460 Hom.: 2 Cov.: 3 AF XY: 0.000615 AC XY: 99 AN XY: 160876

African (AFR) AF: 0.00 AC: 0 AN: 6898

American (AMR) AF: 0.000245 AC: 2 AN: 8168

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10238

East Asian (EAS) AF: 0.00901 AC: 195 AN: 21632

South Asian (SAS) AF: 0.00 AC: 0 AN: 23786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1468

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 193310

Other (OTH) AF: 0.000417 AC: 8 AN: 19178

GnomAD4 genome AF: 0.000217 AC: 33 AN: 152314 Hom.: 1 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74486

African (AFR) AF: 0.00 AC: 0 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15304

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

East Asian (EAS) AF: 0.00620 AC: 32 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000208

Asia WGS AF: 0.00260 AC: 9 AN: 3474

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Arrhythmogenic right ventricular cardiomyopathy (1)
-	-	1	Epidermolysis bullosa simplex due to plakophilin deficiency (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	-0.56
CADD	Benign	13
DANN	Benign	0.96
PhyloP100		0.58
PromoterAI		-0.048	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.0

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: rs547069600; hg19: chr6-7541868;