rs550208733

Positions:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2BP4_StrongBP6BS2

The NM_013352.4(DSE):c.1897G>A(p.Val633Met) variant causes a missense change. The variant allele was found at a frequency of 0.000346 in 1,614,174 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00024 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00036 ( 6 hom. )

Consequence

DSE
NM_013352.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 3.78

Variant links:

Genes affected

DSE (HGNC:21144): (dermatan sulfate epimerase) The protein encoded by this gene is a tumor-rejection antigen. It is localized to the endoplasmic reticulum and functions to convert D-glucuronic acid to L-iduronic acid during the biosynthesis of dermatan sulfate. This antigen possesses tumor epitopes capable of inducing HLA-A24-restricted and tumor-specific cytotoxic T lymphocytes in cancer patients and may be useful for specific immunotherapy. Mutations in this gene cause inmusculocontractural Ehlers-Danlos syndrome. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 9, and a paralogous gene exists on chromosome 18. [provided by RefSeq, Apr 2016]

DSE links:

ENSG00000285446 (HGNC:):

ENSG00000285446 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DSE. . Gene score misZ 2.0252 (greater than the threshold 3.09). Trascript score misZ 3.6915 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, musculocontractural type, Ehlers-Danlos syndrome, musculocontractural type 2.

BP4

Computational evidence support a benign effect (MetaRNN=0.0067157745).

BP6

Variant 6-116436365-G-A is Benign according to our data. Variant chr6-116436365-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 450138.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSE	NM_013352.4 linkuse as main transcript	c.1897G>A	p.Val633Met	missense_variant	6/6	ENST00000644252.3	NP_037484.1	Q9UL01

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSE	ENST00000644252.3 linkuse as main transcript	c.1897G>A	p.Val633Met	missense_variant	6/6		NM_013352.4	ENSP00000494147.2		Q9UL01
ENSG00000285446	ENST00000644499.1 linkuse as main transcript	c.766+5172G>A		intron_variant				ENSP00000495266.1		A0A2R8Y6J1

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

152184

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:

0.00787

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000832

AC:

209

AN:

251264

Hom.:

AF XY:

0.00113

AC XY:

153

AN XY:

135784

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00673

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000356

AC:

521

AN:

1461872

Hom.:

Cov.:

AF XY:

0.000512

AC XY:

372

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00572

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.000397

GnomAD4 genome

AF:

0.000243

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74466

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:

0.00767

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000166

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000914

AC:

111

Asia WGS

AF:

0.00346

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2017

A variant of uncertain significance has been identified in the DSE gene. The V633M variant has not been published as pathogenic or been reported as benign to our knowledge. This variant is observed in 110/16512 (0.7%) alleles from individuals of South Asian ancestry, including one homozygous individual, in the Exome Aggregation Consortium (ExAC) dataset (Lek et al., 2016; Exome Variant Server). The V633M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is only conserved in mammals. Finally, in silico analysis suggests that this variant likely does not alter the protein structure/function. -

Ehlers-Danlos syndrome, musculocontractural type 2

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.060

T;T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.80

LIST_S2

Uncertain

0.92

.;.;D

MetaRNN

Benign

0.0067

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.69

N;N;N

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.060

N;N;.

REVEL

Benign

0.13

Sift

Benign

0.27

T;T;.

Sift4G

Benign

0.25

T;T;.

Polyphen

0.79

P;P;P

Vest4

0.064

MVP

0.70

MPC

0.42

ClinPred

0.10

GERP RS

6.0

Varity_R

0.16

gMVP

0.38

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