rs397516949

Positions:

chr6-7583161-G-A

Variant summary

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

The NM_004415.4(DSP):c.5899G>A(p.Val1967Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,614,002 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. V1967V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

DSP
NM_004415.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.309

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=0.09830153).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
DSP	NM_004415.4 linkuse as main transcript	c.5899G>A	p.Val1967Met	missense_variant	24/24	ENST00000379802.8
DSP	NM_001319034.2 linkuse as main transcript	c.4570G>A	p.Val1524Met	missense_variant	24/24
DSP	NM_001008844.3 linkuse as main transcript	c.4102G>A	p.Val1368Met	missense_variant	24/24

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DSP	ENST00000379802.8 linkuse as main transcript	c.5899G>A	p.Val1967Met	missense_variant	24/24	1	NM_004415.4	P2	P15924-1
DSP	ENST00000418664.2 linkuse as main transcript	c.4102G>A	p.Val1368Met	missense_variant	24/24	1		A2	P15924-2
DSP	ENST00000710359.1 linkuse as main transcript	c.4570G>A	p.Val1524Met	missense_variant	24/24			A2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251246

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135802

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727242

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:

0.00000629

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152116

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000588

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jun 28, 2012

Variant classified as Uncertain Significance - Favor Benign. The Val1967Met vari ant in DSP has not been previously reported in the literature nor previously bee n identified by our laboratory. Valine (Val) at position 1967 is not conserved i n distantly related mammals and the platypus carries a methionine (Met; this var iant) at this position. In addition, computational analyses (biochemical amino a cid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impact the normal function of the protein, though this informat ion is not predictive enough to rule out pathogenicity. Although the lack of con servation and computational data are supportive of a benign role for Val1967Met, additional studies are needed to fully assess its clinical significance. -

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

Nov 30, 2023

- -

Cardiomyopathy

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Color Diagnostics, LLC DBA Color Health

Dec 05, 2023

This missense variant replaces valine with methionine at codon 1967 of the DSP protein. Computational prediction tools and conservation analyses are inconclusive regarding the impact of this variant on the protein function. Computational splicing tools suggest that this variant may not impact RNA splicing. To our knowledge, functional assays have not been performed for this variant nor has this variant been reported in individuals affected with cardiovascular disorders in the literature. This variant has been identified in 3/251246 chromosomes in the general population by the Genome Aggregation Database (gnomAD). 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. -

Arrhythmogenic right ventricular dysplasia 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Nov 04, 2022

The c.5899G>A variant in DSP has not previously been reported in the literature and it has been deposited in ClinVar [ClinVar ID: 44933] as variant of uncertain significance without phenotype information. The c.5899G>A variant is observed in 7 alleles (~0.0012% minor allele frequency with 0 homozygote) in population databases (gnomAD v2.1.1 and v3.1.2, TOPMed Freeze 8), suggesting it is not a common benign variant in the populations represented in those databases. The c.5899G>A variant in DSP is located in exon 24 of this 24-exon gene, and is predicted to replace an evolutionarily weakly conserved valine amino acid with methionine at position 1967 (p.(Val1967Met) in the encoded protein. In silico predictions are not in favor of damaging effect for the p.(Val1967Met) variant [CADD v1.6 =23.2, REVEL = 0.093]; however, there are no functional studies to support or refute these predictions. Based on available evidence this c.5899G>Ap.(Val1967Met) variant identified in DSP is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 23, 2020

The c.5899G>A (p.V1967M) alteration is located in exon 24 (coding exon 24) of the DSP gene. This alteration results from a G to A substitution at nucleotide position 5899, causing the valine (V) at amino acid position 1967 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.

Eigen

Benign

-0.19

Eigen_PC

Benign

0.016

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.92

D;D

M_CAP

Benign

0.013

MetaRNN

Benign

0.098

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;.

MutationTaster

Benign

0.84

N;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.40

N;N

REVEL

Benign

0.093

Sift

Benign

0.054

T;T

Sift4G

Benign

0.10

T;T

Polyphen

0.0070

B;.

Vest4

0.13

MutPred

0.40

Loss of ubiquitination at K1965 (P = 0.0853);.;

MVP

0.17

MPC

0.22

ClinPred

0.28

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.073

gMVP

0.31

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