6-7562999-T-G

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.726+219T>G		intron_variant	Intron 5 of 23	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.726+219T>G		intron_variant	Intron 5 of 23		NP_001305963.1
DSP	NM_001008844.3	c.726+219T>G		intron_variant	Intron 5 of 23		NP_001008844.1
DSP	NM_001406591.1	c.726+219T>G		intron_variant	Intron 5 of 10		NP_001393520.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.726+219T>G		intron_variant	Intron 5 of 23	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.726+219T>G		intron_variant	Intron 5 of 23	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.726+219T>G		intron_variant	Intron 5 of 23			ENSP00000518230.1
DSP	ENST00000506617.1	n.244+219T>G		intron_variant	Intron 2 of 3	3

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

Gnomad4 AFR AF: 0.513

Gnomad4 AMR AF: 0.403

Gnomad4 ASJ AF: 0.415

Gnomad4 EAS AF: 0.467

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.453

Gnomad4 OTH AF: 0.441

Alfa AF: 0.448 Hom.: 20510

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.9
DANN	Benign	0.71

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: rs2076295; hg19: chr6-7563232; COSMIC: COSV65791349;