6-7570477-C-T

Variant names:

• chr6-7570477-C-T
• rs727504498
• NM_004415.4:c.1615C>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_004415.4(DSP):​c.1615C>T​(p.Gln539*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSP NM_004415.4 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.84

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-7570477-C-T is Pathogenic according to our data. Variant chr6-7570477-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 178862.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr6-7570477-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.1615C>T	p.Gln539*	stop_gained	Exon 13 of 24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1615C>T	p.Gln539*	stop_gained	Exon 13 of 24		NP_001305963.1
DSP	NM_001008844.3	c.1615C>T	p.Gln539*	stop_gained	Exon 13 of 24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1615C>T	p.Gln539*	stop_gained	Exon 13 of 24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1615C>T	p.Gln539*	stop_gained	Exon 13 of 24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1615C>T	p.Gln539*	stop_gained	Exon 13 of 24			ENSP00000518230.1
DSP	ENST00000684395.1	n.-2C>T		upstream_gene_variant

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Primary dilated cardiomyopathy Pathogenic:1

Mar 27, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Gln539X variant has not been reported in the literature nor previously ident ified by our laboratory. This variant has also not been identified in large and broad European American and African American populations by the NHLBI Exome Seq uencing Project (http://evs.gs.washington.edu/EVS), which increases the likeliho od that it is pathogenic. However, we cannot exclude that it may be common in ot her populations. This nonsense variant leads to a premature termination codon a t position 539 which is predicted to lead to a truncated or absent protein. Fra meshift and nonsense variants in DSP have been reported in patients with ARVC (h ttp://arvcdatabase.info/), but recent evidence supports that they can also cause DCM (Elliott 2010, Garcia-Pavia 2011). In summary, this variant is likely to b e pathogenic, though additional studies are required to fully establish its clin ical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	39
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
Vest4		0.98
GERP RS		5.8

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

Publications

LitVar

Other links and lift over

dbSNP: rs727504498; hg19: chr6-7570710;