6-7567737-C-T

Position:

• chr6-7567737-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004415.4(DSP):​c.1141-44C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.764 in 1,611,848 control chromosomes in the GnomAD database, including 471,357 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.78 (45824 hom., cov: 31)
  • Exomes 𝑓: 0.76 (425533 hom.)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0290

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 6-7567737-C-T is Benign according to our data. Variant chr6-7567737-C-T is described in ClinVar as [Benign]. Clinvar id is 259381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7567737-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.792 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.1141-44C>T		intron_variant		ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1141-44C>T		intron_variant			NP_001305963.1
DSP	NM_001008844.3	c.1141-44C>T		intron_variant			NP_001008844.1
DSP	NM_001406591.1	c.1141-44C>T		intron_variant			NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1141-44C>T		intron_variant		1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1141-44C>T		intron_variant		1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1141-44C>T		intron_variant				ENSP00000518230.1
DSP	ENST00000682228.1	n.752C>T		non_coding_transcript_exon_variant	3/3

Frequencies

GnomAD3 genomes AF: 0.775 AC: 117801 AN: 151956 Hom.: 45804 Cov.: 31

Gnomad AFR AF: 0.797

Gnomad AMI AF: 0.784

Gnomad AMR AF: 0.781

Gnomad ASJ AF: 0.843

Gnomad EAS AF: 0.813

Gnomad SAS AF: 0.686

Gnomad FIN AF: 0.717

Gnomad MID AF: 0.813

Gnomad NFE AF: 0.769

Gnomad OTH AF: 0.779

GnomAD3 exomes AF: 0.760 AC: 190311 AN: 250490 Hom.: 72656 AF XY: 0.756 AC XY: 102337 AN XY: 135424

Gnomad AFR exome AF: 0.800

Gnomad AMR exome AF: 0.767

Gnomad ASJ exome AF: 0.835

Gnomad EAS exome AF: 0.805

Gnomad SAS exome AF: 0.681

Gnomad FIN exome AF: 0.714

Gnomad NFE exome AF: 0.767

Gnomad OTH exome AF: 0.769

GnomAD4 exome AF: 0.763 AC: 1113092 AN: 1459774 Hom.: 425533 Cov.: 36 AF XY: 0.761 AC XY: 552552 AN XY: 726266

Gnomad4 AFR exome AF: 0.797

Gnomad4 AMR exome AF: 0.772

Gnomad4 ASJ exome AF: 0.834

Gnomad4 EAS exome AF: 0.834

Gnomad4 SAS exome AF: 0.684

Gnomad4 FIN exome AF: 0.713

Gnomad4 NFE exome AF: 0.765

Gnomad4 OTH exome AF: 0.773

GnomAD4 genome AF: 0.775 AC: 117866 AN: 152074 Hom.: 45824 Cov.: 31 AF XY: 0.773 AC XY: 57405 AN XY: 74306

Gnomad4 AFR AF: 0.797

Gnomad4 AMR AF: 0.781

Gnomad4 ASJ AF: 0.843

Gnomad4 EAS AF: 0.812

Gnomad4 SAS AF: 0.686

Gnomad4 FIN AF: 0.717

Gnomad4 NFE AF: 0.769

Gnomad4 OTH AF: 0.775

Alfa AF: 0.769 Hom.: 9595

Bravo AF: 0.786

Asia WGS AF: 0.699 AC: 2431 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Woolly hair-skin fragility syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Keratosis palmoplantaris striata 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.9
DANN	Benign	0.43
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs2076296; hg19: chr6-7567970; COSMIC: COSV65793236; COSMIC: COSV65793236;