rs397516922

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004415.4(DSP):c.2134G>A(p.Val712Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. V712L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 2.33

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 Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.174391).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSP	NM_004415.4 linkuse as main transcript	c.2134G>A	p.Val712Met	missense_variant	16/24	ENST00000379802.8
DSP	NM_001319034.2 linkuse as main transcript	c.2134G>A	p.Val712Met	missense_variant	16/24
DSP	NM_001008844.3 linkuse as main transcript	c.2134G>A	p.Val712Met	missense_variant	16/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.2134G>A	p.Val712Met	missense_variant	16/24	1	NM_004415.4	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.2134G>A	p.Val712Met	missense_variant	16/24	1		A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.2134G>A	p.Val712Met	missense_variant	16/24			A2
DSP	ENST00000684395.1 linkuse as main transcript	n.775G>A		non_coding_transcript_exon_variant	3/5

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251274

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

727172

show subpopulations

Gnomad4 AFR exome

AF:

0.000418

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000105

AC:

AN:

152214

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 05, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 15, 2012	The Val712Met variant in DSP has not been reported in the literature nor previou sly identified by our laboratory. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) do not provide strong support for or against an impact to the protein. Additional information is need ed to fully assess the clinical significance of the Val712Met variant. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Mar 23, 2021

- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 24, 2021

The c.2134G>A (p.V712M) alteration is located in exon 16 (coding exon 16) of the DSP gene. This alteration results from a G to A substitution at nucleotide position 2134, causing the valine (V) at amino acid position 712 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

DSP-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 17, 2022

The DSP c.2134G>A variant is predicted to result in the amino acid substitution p.Val712Met. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.024% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/6-7574322-G-A). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Mar 30, 2021

DSP NM_004415.3 exon 16 p.Val712Met (c.2134G>A): This variant has not been reported in the literature and is present in 0.02% (6/24970) of African alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/6-7574322-G-A). This variant is present in ClinVar (Variation ID:44871). Evolutionary conservation and computational predictive tools for this variant are unclear. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.16

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.28

T;.

Eigen

Benign

-0.23

Eigen_PC

Benign

-0.074

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.17

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

N;N

MutationTaster

Benign

0.99

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.2

N;N

REVEL

Uncertain

0.32

Sift

Uncertain

0.0080

D;D

Sift4G

Uncertain

0.015

D;D

Polyphen

0.43

B;.

Vest4

0.49

MVP

0.83

MPC

0.34

ClinPred

0.13

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.095

gMVP

0.30

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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