chr6-7570558-G-A

Position:

• chr6-7570558-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_004415.4(DSP):​c.1696G>A​(p.Ala566Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000303 in 1,612,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:12 O:1
• Conservation: PhyloP100: 5.00

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 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13894385).
• BP6: Variant 6-7570558-G-A is Benign according to our data. Variant chr6-7570558-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161226.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=8, Uncertain_significance=5, not_provided=1}. Variant chr6-7570558-G-A is described in Lovd as [Benign]. Variant chr6-7570558-G-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSP	NM_004415.4	c.1696G>A	p.Ala566Thr	missense_variant	13/24	ENST00000379802.8	NP_004406.2
DSP	NM_001319034.2	c.1696G>A	p.Ala566Thr	missense_variant	13/24		NP_001305963.1
DSP	NM_001008844.3	c.1696G>A	p.Ala566Thr	missense_variant	13/24		NP_001008844.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSP	ENST00000379802.8	c.1696G>A	p.Ala566Thr	missense_variant	13/24	1	NM_004415.4	ENSP00000369129.3
DSP	ENST00000418664.2	c.1696G>A	p.Ala566Thr	missense_variant	13/24	1		ENSP00000396591.2
DSP	ENST00000710359.1	c.1696G>A	p.Ala566Thr	missense_variant	13/24			ENSP00000518230.1
DSP	ENST00000684395.1	n.80G>A		non_coding_transcript_exon_variant	1/5

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152144 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000471

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000199 AC: 50 AN: 251036 Hom.: 0 AF XY: 0.000221 AC XY: 30 AN XY: 135668

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.000232

Gnomad NFE exome AF: 0.000335

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000307 AC: 448 AN: 1460666 Hom.: 0 Cov.: 32 AF XY: 0.000307 AC XY: 223 AN XY: 726638

Gnomad4 AFR exome AF: 0.0000897

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.000281

Gnomad4 NFE exome AF: 0.000366

Gnomad4 OTH exome AF: 0.000166

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152262 Hom.: 0 Cov.: 32 AF XY: 0.000282 AC XY: 21 AN XY: 74450

Gnomad4 AFR AF: 0.0000963

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000471

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000436 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:7 Benign:12 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 2024	Published in association with ARVC, HCM, and DCM, and found to independently segregate with disease in a relative of a proband with ARVC (PMID: 16774985, 21606396, 27000522, 25351510, 28045975); Functional studies suggest that the p.(A566T) variant alone is insufficient to impair protein function (PMID: 25225338); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 25637381, 24055113, 21606396, 23299917, 26332594, 25351510, 28045975, 31402444, 26606670, 31785789, 36142674, 22949226, 33652588, 35653365, 16774985, 27000522, 25225338) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 16, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 08, 2022	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Dec 05, 2017	p.Ala566Thr in exon 13 of DSP: This variant is not expected to have clinical sig nificance because it has been identified in 0.03% (40/126324) of European chrom osomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute .org; dbSNP ${MatchVariant_1_dbSNPrsNumber}). ACMG/AMP Criteria applied: BS1. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 10, 2024	Variant summary: DSP c.1696G>A (p.Ala566Thr) results in a non-conservative amino acid change located in the spectrin-like domain (IPR041573) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251036 control chromosomes, predominantly at a frequency of 0.00034 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.7 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy phenotype (0.0002). The variant, c.1696G>A, has been reported in the literature in individuals affected with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy and other cardiac phenotypes, however several of these reported affected individuals carried a co-occurring (likely) pathogenic variant, which could explain the phenotype (e.g. Cox_2011, Begay_2016, Franaszczyk_2017). These reports do not provide unequivocal conclusions about association of the variant with Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy. At least one publication reported experimental evidence evaluating an impact on protein function and demonstrated no significant changes for the A566T variant (Patel_2014). The following publications have been ascertained in the context of this evaluation (PMID: 21606396, 28008423, 28045975, 25225338). ClinVar contains an entry for this variant (Variation ID: 161226). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Arrhythmogenic right ventricular dysplasia 8 Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 31, 2019	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Uncertain significance, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	Jun 18, 2018	- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, no assertion criteria provided

research

CSER _CC_NCGL, University of Washington

Jun 01, 2014

- -

Skin fragility with non-scarring blistering;C4024876:Palmoplantar blistering Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Jan 01, 2017

- -

Woolly hair-skin fragility syndrome;C1843896:Arrhythmogenic right ventricular dysplasia 8;C1852127:Keratosis palmoplantaris striata 2;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C1864826:Lethal acantholytic epidermolysis bullosa;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 19, 2024

- -

Cardiomyopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Nov 13, 2019

- -

Lethal acantholytic epidermolysis bullosa Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 31, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Woolly hair-skin fragility syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 31, 2019

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2022

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. -

Arrhythmogenic right ventricular dysplasia 8;C1854063:Arrhythmogenic cardiomyopathy with wooly hair and keratoderma;C4014393:Cardiomyopathy, dilated, with wooly hair, keratoderma, and tooth agenesis Other:1

not provided, no classification provided

phenotyping only

GenomeConnect - Invitae Patient Insights Network

-

Variant interpreted as Uncertain significance and reported on 12-28-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Uncertain	-0.040
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Benign	0.021
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.25	N;N
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.26
Sift	Benign	0.084	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.40	B;.
Vest4		0.87
MVP		0.92
MPC		0.78
ClinPred		0.043	T
GERP RS		5.7
Varity_R		0.28
gMVP		0.41

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: rs148147581; hg19: chr6-7570791; COSMIC: COSV101131275; COSMIC: COSV101131275;