NM_004415.4:c.726+219T>G

Variant names:

• chr6-7562999-T-G
• rs2076295
• NM_004415.4:c.726+219T>G

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.726+219T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 152,042 control chromosomes in the GnomAD database, including 15,880 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.45 (15880 hom., cov: 32)
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign criteria provided, single submitter P:1 U:1 B:1 O:2
• Conservation: PhyloP100: -0.0580
• Publications: 91 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=-0.88).
• BP6: Variant 6-7562999-T-G is Benign according to our data. Variant chr6-7562999-T-G is described in ClinVar as Benign. ClinVar VariationId is 672128.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.507 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	NM_004415.4	MANE Select	c.726+219T>G		intron	N/A	NP_004406.2
	DSP	NM_001319034.2		c.726+219T>G		intron	N/A	NP_001305963.1
	DSP	NM_001008844.3		c.726+219T>G		intron	N/A	NP_001008844.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DSP	ENST00000379802.8	TSL:1 MANE Select	c.726+219T>G		intron	N/A	ENSP00000369129.3
	DSP	ENST00000418664.3	TSL:1	c.726+219T>G		intron	N/A	ENSP00000396591.2
	DSP	ENST00000713904.1		c.600+219T>G		intron	N/A	ENSP00000519203.1

Frequencies

GnomAD3 genomes AF: 0.453 AC: 68786 AN: 151924 Hom.: 15842 Cov.: 32

Gnomad AFR AF: 0.512

Gnomad AMI AF: 0.357

Gnomad AMR AF: 0.403

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.467

Gnomad SAS AF: 0.331

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.453

Gnomad OTH AF: 0.445

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.453 AC: 68868 AN: 152042 Hom.: 15880 Cov.: 32 AF XY: 0.443 AC XY: 32896 AN XY: 74338

African (AFR) AF: 0.513 AC: 21258 AN: 41454

American (AMR) AF: 0.403 AC: 6161 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3472

East Asian (EAS) AF: 0.467 AC: 2414 AN: 5168

South Asian (SAS) AF: 0.330 AC: 1593 AN: 4826

European-Finnish (FIN) AF: 0.366 AC: 3862 AN: 10562

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.453 AC: 30780 AN: 67954

Other (OTH) AF: 0.441 AC: 933 AN: 2116

Alfa AF: 0.455 Hom.: 47899

Bravo AF: 0.465

Asia WGS AF: 0.385 AC: 1341 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Uncertain:1 Benign:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Susceptibility to severe coronavirus disease (COVID-19) Pathogenic:1

May 13, 2024

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Likely risk allele

Review Status: no assertion criteria provided

Collection Method: research

The NC_000006.12:g.7562999T>G (rs2076295) is a noncoding intron variant in DSP (desmoplakin). It has been related to the susceptibility of idiopathic pulmonary fibrosis in genome-wide association studies (PMID: 31710517). The G allele was found associated with non-survival risk in the linear regression analysis adjusting for age, SAH, cardiopathies, CRD, PaO2/FiO2 at admission, and the IMV requirement (p=0.047), even when age, PaO2/FiO2, and IMV requirement were only considered as co-variables (p=0.039). Additionally, the TG genotype was found to have a low risk of death when the last three variables were included as co-variables in the analysis (p=0.011, OR=0.58, 95%CI = 0.39-0.88), as well as for the TT+TG genotypes (p=0.021, OR=0.63, 95%CI = 0.43-0.93). However, carriers of this allele in the patients with post-COVID-19 condition presented higher scores on the pulmonary function tests at different follow-ups (FEV1/FVC, FVC %, FEV1 %, and ∆SpO2) than those carrying the T allele. Due to the reported data, the variant was classified as a likely risk allele.

Chronic obstructive pulmonary disease Uncertain:1

May 04, 2021

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: case-control

not provided Benign:1

Jun 14, 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.

Interstitial lung disease 2 Other:1

May 04, 2021

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: association

Review Status: no assertion criteria provided

Collection Method: case-control

Combined pulmonary fibrosis-emphysema syndrome Other:1

May 04, 2021

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: association

Review Status: no assertion criteria provided

Collection Method: case-control

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.9
DANN	Benign	0.71
PhyloP100		-0.058
Mutation Taster		=98/2	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: rs2076295; hg19: chr6-7563232; COSMIC: COSV65791349;