rs397516971

chr6-7585755-GGGATCTCGCTCC-Gchr6-7585755-GGGATCTCGCTCC-GGGATCTCGCTCCGGATCTCGCTCC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM4 PP3 BP6

The NM_004415.4(DSP):c.8508_8519del(p.Ser2843_Arg2846del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000201 in 1,609,570 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G2832G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (1 hom.)
• Consequence: DSP NM_004415.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 8.12

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 Uncertain_significance. Variant got 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_004415.4.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• BP6: Variant 6-7585755-GGGATCTCGCTCC-G is Benign according to our data. Variant chr6-7585755-GGGATCTCGCTCC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44975.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.8508_8519del	p.Ser2843_Arg2846del	inframe_deletion	24/24	ENST00000379802.8
DSP	NM_001008844.3	c.6711_6722del	p.Ser2244_Arg2247del	inframe_deletion	24/24
DSP	NM_001319034.2	c.7179_7190del	p.Ser2400_Arg2403del	inframe_deletion	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.8508_8519del	p.Ser2843_Arg2846del	inframe_deletion	24/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.6711_6722del	p.Ser2244_Arg2247del	inframe_deletion	24/24	1		A2
DSP	ENST00000710359.1	c.7179_7190del	p.Ser2400_Arg2403del	inframe_deletion	24/24			A2

Frequencies

GnomAD3 genomes AF: 0.000500 AC: 76 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000243 AC: 60 AN: 246768 Hom.: 0 AF XY: 0.000262 AC XY: 35 AN XY: 133792

Gnomad AFR exome AF: 0.00119

Gnomad AMR exome AF: 0.0000889

Gnomad ASJ exome AF: 0.000102

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000233

Gnomad FIN exome AF: 0.0000466

Gnomad NFE exome AF: 0.000251

Gnomad OTH exome AF: 0.000167

GnomAD4 exome AF: 0.000169 AC: 247 AN: 1457364 Hom.: 1 AF XY: 0.000155 AC XY: 112 AN XY: 724800

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.0000909

Gnomad4 ASJ exome AF: 0.0000772

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000175

Gnomad4 FIN exome AF: 0.000150

Gnomad4 NFE exome AF: 0.000145

Gnomad4 OTH exome AF: 0.000233

GnomAD4 genome AF: 0.000506 AC: 77 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74432

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000416

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.000552

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	This variant is associated with the following publications: (PMID: 27532257, 24503780, 21636032, 25445213, 31402444) -
Uncertain significance, criteria provided, single submitter	clinical testing	Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Feb 18, 2015	p.Ser2843_Arg2846del in exon 24 of DSP: This variant is not expected to have cli nical significance because it has been identified in 0.4% (50/11494) of Latino c hromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute .org). This in-frame deletion of four amino acids occurs within a region of repe ating amino acids. It can result from several different DNA deletions, and is pr esent in mammals (dolphin, opossum, and platypus) and other evolutionarily dista nt species. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 08, 2019	Variant summary: DSP c.8508_8519del12 (p.Ser2843_Arg2846del) results in an in-frame deletion that is predicted to remove four amino acids from a repetitive region at the C-terminus of the protein (of note, this protein level change can be a result of several different DNA deletions). The variant allele was found at a frequency of 0.0003 in 278122 control chromosomes, predominantly at a frequency of 0.0015 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 7.5 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. Though the variant has been reported in the literature in one individual affected with Arrhythmogenic Right Ventricular Cardiomyopathy (Green_2014), it was also described in a healthy control (Kapplinger_2011). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three ClinVar submitters (evaluation after 2014) classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as benign. -

Cardiomyopathy Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 09, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Mar 04, 2021	- -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 07, 2018

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs397516971; hg19: chr6-7585988;