rs3778337

Variant names:

• chr6-7565652-G-A
• rs3778337
• NM_004415.4:c.939+132G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-7565652-G-A
• chr6-7565652-G-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_004415.4(DSP):​c.939+132G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.284 in 1,247,782 control chromosomes in the GnomAD database, including 52,232 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.27 (5759 hom., cov: 32)
  • Exomes 𝑓: 0.29 (46473 hom.)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.01
• Publications: 8 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):

• arrhythmogenic right ventricular dysplasia 8

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• keratosis palmoplantaris striata 2

  Inheritance: AD Classification: DEFINITIVE, STRONG, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp
• skin fragility-woolly hair-palmoplantar keratoderma syndrome

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Orphanet, G2P, Genomics England PanelApp, Ambry Genetics
• arrhythmogenic cardiomyopathy with wooly hair and keratoderma

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

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• lethal acantholytic epidermolysis bullosa

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: PanelApp Australia, 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 (BayesDel_noAF=-1.01).
• BP6: Variant 6-7565652-G-A is Benign according to our data. Variant chr6-7565652-G-A is described in ClinVar as Benign. ClinVar VariationId is 672129.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.444 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.939+132G>A		intron_variant	Intron 7 of 23	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.939+132G>A		intron_variant	Intron 7 of 23		NP_001305963.1
DSP	NM_001008844.3	c.939+132G>A		intron_variant	Intron 7 of 23		NP_001008844.1
DSP	NM_001406591.1	c.939+132G>A		intron_variant	Intron 7 of 10		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.939+132G>A		intron_variant	Intron 7 of 23	1	NM_004415.4	ENSP00000369129.3

Frequencies

GnomAD3 genomes AF: 0.268 AC: 40722 AN: 151956 Hom.: 5753 Cov.: 32

Gnomad AFR AF: 0.225

Gnomad AMI AF: 0.283

Gnomad AMR AF: 0.285

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.459

Gnomad SAS AF: 0.261

Gnomad FIN AF: 0.208

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.288

Gnomad OTH AF: 0.267

GnomAD4 exome AF: 0.286 AC: 313046 AN: 1095708 Hom.: 46473 Cov.: 14 AF XY: 0.285 AC XY: 157051 AN XY: 551438

African (AFR) AF: 0.226 AC: 5792 AN: 25582

American (AMR) AF: 0.329 AC: 11197 AN: 34062

Ashkenazi Jewish (ASJ) AF: 0.227 AC: 5105 AN: 22530

East Asian (EAS) AF: 0.476 AC: 16411 AN: 34508

South Asian (SAS) AF: 0.257 AC: 18642 AN: 72474

European-Finnish (FIN) AF: 0.217 AC: 9012 AN: 41530

Middle Eastern (MID) AF: 0.276 AC: 948 AN: 3440

European-Non Finnish (NFE) AF: 0.286 AC: 232430 AN: 813798

Other (OTH) AF: 0.283 AC: 13509 AN: 47784

GnomAD4 genome AF: 0.268 AC: 40741 AN: 152074 Hom.: 5759 Cov.: 32 AF XY: 0.266 AC XY: 19782 AN XY: 74348

African (AFR) AF: 0.225 AC: 9324 AN: 41474

American (AMR) AF: 0.285 AC: 4363 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 766 AN: 3466

East Asian (EAS) AF: 0.459 AC: 2377 AN: 5176

South Asian (SAS) AF: 0.260 AC: 1252 AN: 4818

European-Finnish (FIN) AF: 0.208 AC: 2198 AN: 10580

Middle Eastern (MID) AF: 0.223 AC: 65 AN: 292

European-Non Finnish (NFE) AF: 0.288 AC: 19581 AN: 67964

Other (OTH) AF: 0.264 AC: 557 AN: 2108

Alfa AF: 0.284 Hom.: 5189

Bravo AF: 0.279

Asia WGS AF: 0.320 AC: 1114 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.077
DANN	Benign	0.59
PhyloP100		-3.0
Mutation Taster		=100/0	polymorphism (auto)

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: rs3778337; hg19: chr6-7565885;