6-7575273-CTT-CT

Variant names:

• chr6-7575273-CT-C
• rs727502998
• NM_004415.4:c.2437-11delT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_004415.4(DSP):​c.2437-11delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0259 in 817,948 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00092 (3 hom., cov: 33)
  • Exomes 𝑓: 0.026 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DSP NM_004415.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.0620

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP6: Variant 6-7575273-CT-C is Benign according to our data. Variant chr6-7575273-CT-C is described in ClinVar as [Benign]. Clinvar id is 163253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-7575273-CT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0259 (21176/817948) while in subpopulation AMR AF = 0.0415 (925/22266). AF 95% confidence interval is 0.0393. There are 0 homozygotes in GnomAdExome4. There are 10511 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DSP	NM_004415.4	c.2437-11delT		intron_variant	Intron 17 of 23	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.2437-11delT		intron_variant	Intron 17 of 23		NP_001305963.1
DSP	NM_001008844.3	c.2437-11delT		intron_variant	Intron 17 of 23		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.2437-21delT		intron_variant	Intron 17 of 23	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.2437-21delT		intron_variant	Intron 17 of 23	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.2437-21delT		intron_variant	Intron 17 of 23			ENSP00000518230.1
DSP	ENST00000684395.1	n.1078-21delT		intron_variant	Intron 4 of 4

Frequencies

GnomAD3 genomes AF: 0.000822 AC: 121 AN: 147218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00159

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000951

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000214

Gnomad FIN AF: 0.00148

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000406

Gnomad OTH AF: 0.000503

GnomAD2 exomes AF: 0.0680 AC: 5778 AN: 84998 AF XY: 0.0687

Gnomad AFR exome AF: 0.0581

Gnomad AMR exome AF: 0.0621

Gnomad ASJ exome AF: 0.0557

Gnomad EAS exome AF: 0.0572

Gnomad FIN exome AF: 0.0528

Gnomad NFE exome AF: 0.0757

Gnomad OTH exome AF: 0.0588

GnomAD4 exome AF: 0.0259 AC: 21176 AN: 817948 Hom.: 0 Cov.: 30 AF XY: 0.0260 AC XY: 10511 AN XY: 403684

Gnomad4 AFR exome AF: 0.0321 AC: 584 AN: 18206

Gnomad4 AMR exome AF: 0.0415 AC: 925 AN: 22266

Gnomad4 ASJ exome AF: 0.0341 AC: 436 AN: 12800

Gnomad4 EAS exome AF: 0.0338 AC: 649 AN: 19174

Gnomad4 SAS exome AF: 0.0248 AC: 1097 AN: 44188

Gnomad4 FIN exome AF: 0.0344 AC: 946 AN: 27530

Gnomad4 NFE exome AF: 0.0243 AC: 15492 AN: 637162

Gnomad4 Remaining exome AF: 0.0294 AC: 969 AN: 32918

⚠️ The allele balance in gnomAD4 Exomes is highly skewed (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.000923 AC: 136 AN: 147288 Hom.: 3 Cov.: 33 AF XY: 0.00100 AC XY: 72 AN XY: 71670

Gnomad4 AFR AF: 0.00196 AC: 0.00195816 AN: 0.00195816

Gnomad4 AMR AF: 0.000950 AC: 0.000950183 AN: 0.000950183

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000215 AC: 0.000214684 AN: 0.000214684

Gnomad4 FIN AF: 0.00148 AC: 0.00148211 AN: 0.00148211

Gnomad4 NFE AF: 0.000406 AC: 0.000406492 AN: 0.000406492

Gnomad4 OTH AF: 0.000499 AC: 0.000498504 AN: 0.000498504

Alfa AF: 0.0682 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Apr 20, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

2437-11delT in intron 17 of DSP: This variant is not expected to have clinical s ignificance because it has been identified in 18% (1498/8254) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS). -

not provided Benign:2

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hypertrophic cardiomyopathy 2 Other:1

-

Institute of Human Genetics, University of Wuerzburg

Significance: not provided

Review Status: no classification provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
Mutation Taster		=100/0	polymorphism

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: rs727502998; hg19: chr6-7575506; COSMIC: COSV65793555;