rs372922674

Positions:

chr6-7576964-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The NM_004415.4(DSP):c.2799G>C(p.Leu933Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000105 in 1,612,978 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L933L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 2.20

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSP	NM_004415.4 linkuse as main transcript	c.2799G>C	p.Leu933Phe	missense_variant	20/24	ENST00000379802.8
DSP	NM_001319034.2 linkuse as main transcript	c.2799G>C	p.Leu933Phe	missense_variant	20/24
DSP	NM_001008844.3 linkuse as main transcript	c.2799G>C	p.Leu933Phe	missense_variant	20/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.2799G>C	p.Leu933Phe	missense_variant	20/24	1	NM_004415.4	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.2799G>C	p.Leu933Phe	missense_variant	20/24	1		A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.2799G>C	p.Leu933Phe	missense_variant	20/24			A2

Frequencies

GnomAD3 genomes

AF:

0.0000920

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000191

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000678

AC:

AN:

250856

Hom.:

AF XY:

0.0000885

AC XY:

AN XY:

135562

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

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:

0.000141

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000107

AC:

156

AN:

1460824

Hom.:

Cov.:

AF XY:

0.000109

AC XY:

AN XY:

726638

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.000131

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152154

Hom.:

Cov.:

AF XY:

0.0000942

AC XY:

AN XY:

74330

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000310

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000547

EpiControl

AF:

0.000297

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Cardiomyopathy

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Feb 23, 2023	This missense variant replaces leucine with phenylalanine at codon 933 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 been reported in an individual affected with arrhythmogenic right ventricular cardiomyopathy (PMID: 27532257). This variant has been identified in 21/282260 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	Jan 08, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 11, 2017

The p.Leu933Phe variant in DSP has been reported in 1 individual with ARVC (Wals h 2016). This variant has also been reported in ClinVar (Variation ID 265104). T his variant has been identified in 8/65790 European chromosomes by the Exome Agg regation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs372922674). C omputational prediction tools and conservation analysis do not provide strong su pport for or against an impact to the protein. In summary, the clinical signific ance of the p.Leu933Phe variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2021

Observed in an individual with ARVC and classified as a variant of unknown pathogenicity in the published literature (Walsh et al., 2017; Ye et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID 265104; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 26582918, 27532257, 27535533, 31402444) -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2023

The p.L933F variant (also known as c.2799G>C), located in coding exon 20 of the DSP gene, results from a G to C substitution at nucleotide position 2799. The leucine at codon 933 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was identified in a cohort that underwent genetic testing for arrhythmogenic right ventricular cardiomyopathy; however, clinical details were limited (Walsh R et al. Genet. Med., 2017 02;19:192-203). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Nov 01, 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 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Benign

-0.054

BayesDel_noAF

Uncertain

-0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.74

D;D

MetaSVM

Benign

-0.98

MutationAssessor

Uncertain

2.4

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.3

D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0040

D;D

Sift4G

Uncertain

0.012

D;D

Polyphen

0.99

D;.

Vest4

0.80

MutPred

0.32

Loss of ubiquitination at K931 (P = 0.0877);Loss of ubiquitination at K931 (P = 0.0877);

MVP

0.71

MPC

0.86

ClinPred

0.68

GERP RS

4.0

Varity_R

0.24

gMVP

0.59

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over