6-7579806-T-A

Position:

• chr6-7579806-T-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.3616T>A​(p.Leu1206Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000088 in 1,613,524 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1206V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000092 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: DSP NM_004415.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 2.32

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 Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15024301).
• BP6: Variant 6-7579806-T-A is Benign according to our data. Variant chr6-7579806-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 199839.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DSP	NM_004415.4	c.3616T>A	p.Leu1206Ile	missense_variant	23/24	ENST00000379802.8
DSP	NM_001319034.2	c.3616T>A	p.Leu1206Ile	missense_variant	23/24
DSP	NM_001008844.3	c.3582+34T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8	c.3616T>A	p.Leu1206Ile	missense_variant	23/24	1	NM_004415.4	P2
DSP	ENST00000418664.2	c.3582+34T>A		intron_variant		1		A2
DSP	ENST00000710359.1	c.3616T>A	p.Leu1206Ile	missense_variant	23/24			A2

Frequencies

GnomAD3 genomes AF: 0.0000923 AC: 14 AN: 151668 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000916 AC: 23 AN: 251146 Hom.: 0 AF XY: 0.000110 AC XY: 15 AN XY: 135766

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000185

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000876 AC: 128 AN: 1461856 Hom.: 0 Cov.: 32 AF XY: 0.0000894 AC XY: 65 AN XY: 727226

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000108

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.0000923 AC: 14 AN: 151668 Hom.: 0 Cov.: 32 AF XY: 0.000122 AC XY: 9 AN XY: 74050

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.0000657

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000182 Hom.: 0

Bravo AF: 0.0000793

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000906 AC: 11

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Cardiomyopathy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 05, 2023	This missense variant replaces leucine with isoleucine at codon 1206 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 26/282508 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Sep 20, 2021	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 35882527, 29253866) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 10, 2017	- -

Arrhythmogenic cardiomyopathy with wooly hair and keratoderma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

All of Us Research Program, National Institutes of Health

Dec 18, 2023

This missense variant replaces leucine with isoleucine at codon 1206 of the DSP protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 26/282508 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Dilated cardiomyopathy 1S Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Institut für Laboratoriums- und Transfusionsmedizin, Herz- und Diabeteszentrum Nordrhein-Westfalen

May 01, 2016

- -

Arrhythmogenic right ventricular cardiomyopathy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Nov 16, 2015

- -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2023

The p.L1206I variant (also known as c.3616T>A), located in coding exon 23 of the DSP gene, results from a T to A substitution at nucleotide position 3616. The leucine at codon 1206 is replaced by isoleucine, an amino acid with highly similar properties. This variant has been reported in an individual with dilated cardiomyopathy (Klauke B et al. PLoS One, 2017 Dec;12:e0189489). This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Oct 15, 2018

Variant summary: DSP c.3616T>A (p.Leu1206Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 9e-05 in 276874 control chromosomes, predominantly at a frequency of 0.00019 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 19 fold of the estimated maximal expected allele frequency for a pathogenic variant in DSP causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3616T>A has been reported in the literature in a DCM family segregating with a likely pathogenic (class IV) RBM20 variant, p.Ser635Cys that the authors believed to be the cause for disease (Klauke_2017). This DSP variant was classified as a VUS (class 3 variant) and was reportedly identified in all genetically tested family members in this study. We interpret this to mean that the variant was present in both affected (i.e., the RBM20 variant positive) and unaffected (i.e., the RBM20 negative) members of this DCM kindred. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. -

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

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.073
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	0.94	D;D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.27
Sift	Benign	0.15	T
Sift4G	Benign	0.41	T
Polyphen		0.0010	B
Vest4		0.32
MVP		0.59
MPC		0.26
ClinPred		0.049	T
GERP RS		4.0
Varity_R		0.069
gMVP		0.26

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: rs151115778; hg19: chr6-7580039;