NM_004415.4:c.-70C>T

Variant names:

• chr6-7541846-C-T
• rs1757982573
• NM_004415.4:c.-70C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004415.4(DSP):​c.-70C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000727 in 1,375,470 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 Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: DSP NM_004415.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.538
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).

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.-70C>T		5_prime_UTR	Exon 1 of 24	NP_004406.2	P15924-1
	DSP	NM_001319034.2		c.-70C>T		5_prime_UTR	Exon 1 of 24	NP_001305963.1	P15924-3
	DSP	NM_001008844.3		c.-70C>T		5_prime_UTR	Exon 1 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.-70C>T		5_prime_UTR	Exon 1 of 24	ENSP00000369129.3	P15924-1
	DSP	ENST00000418664.3	TSL:1	c.-70C>T		5_prime_UTR	Exon 1 of 24	ENSP00000396591.2	P15924-2
	DSP	ENST00000710359.2		c.-70C>T		5_prime_UTR	Exon 1 of 24	ENSP00000518230.1	P15924-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.27e-7 AC: 1 AN: 1375470 Hom.: 0 Cov.: 29 AF XY: 0.00000148 AC XY: 1 AN XY: 676256

African (AFR) AF: 0.00 AC: 0 AN: 31084

American (AMR) AF: 0.00 AC: 0 AN: 35996

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23896

East Asian (EAS) AF: 0.00 AC: 0 AN: 35800

South Asian (SAS) AF: 0.00 AC: 0 AN: 76030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 9.35e-7 AC: 1 AN: 1069090

Other (OTH) AF: 0.00 AC: 0 AN: 56896

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Arrhythmogenic right ventricular dysplasia 8 (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
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.8
DANN	Benign	0.87
PhyloP100		-0.54
PromoterAI		-0.020	Neutral
Mutation Taster		=300/0	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: rs1757982573; hg19: chr6-7542079;