chr6-116431082-A-G

Position:

• chr6-116431082-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP5

The NM_013352.4(DSE):​c.799A>G​(p.Arg267Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSE NM_013352.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.40

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant 6-116431082-A-G is Pathogenic according to our data. Variant chr6-116431082-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 446171.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr6-116431082-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSE	NM_013352.4	c.799A>G	p.Arg267Gly	missense_variant	4/6	ENST00000644252.3	NP_037484.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSE	ENST00000644252.3	c.799A>G	p.Arg267Gly	missense_variant	4/6		NM_013352.4	ENSP00000494147	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Ehlers-Danlos syndrome, musculocontractural type 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 08, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D;D;D;.;.
Eigen	Benign	0.16
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.93	.;.;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	N;N;.;N;.
REVEL	Pathogenic	0.74
Sift	Benign	0.13	T;T;.;T;.
Sift4G	Uncertain	0.0050	D;D;.;D;.
Polyphen		1.0	D;D;D;.;.
Vest4		0.92
MVP		0.41
MPC		1.0
ClinPred		0.95	D
GERP RS		2.2
Varity_R		0.68
gMVP		0.93

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: rs1554227382; hg19: chr6-116752245;