chr6-7562999-T-G

Position:

• chr6-7562999-T-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 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/exons	MANE	UniProt
DSP	NM_004415.4	c.726+219T>G		intron_variant		ENST00000379802.8
DSP	NM_001008844.3	c.726+219T>G		intron_variant
DSP	NM_001319034.2	c.726+219T>G		intron_variant
DSP	NM_001406591.1	c.726+219T>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.726+219T>G		intron_variant		1	NM_004415.4	P2
DSP	ENST00000418664.2	c.726+219T>G		intron_variant		1		A2
DSP	ENST00000710359.1	c.726+219T>G		intron_variant				A2
DSP	ENST00000506617.1	n.244+219T>G		intron_variant, non_coding_transcript_variant		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: Uncertain:1 Benign:1 Other:2

Revision: criteria provided, single submitter

Submissions by phenotype

Chronic obstructive pulmonary disease Uncertain:1

Uncertain significance, no assertion criteria provided

case-control

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 04, 2021

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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. -

Interstitial lung disease 2 Other:1

association, no assertion criteria provided

case-control

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 04, 2021

- -

Combined pulmonary fibrosis-emphysema syndrome Other:1

association, no assertion criteria provided

case-control

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

May 04, 2021

- -

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;