rs1554228151

Positions:

• chr6-116435967-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_013352.4(DSE):​c.1499G>A​(p.Gly500Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DSE NM_013352.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.87

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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DSE	NM_013352.4	c.1499G>A	p.Gly500Asp	missense_variant	6/6	ENST00000644252.3	NP_037484.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DSE	ENST00000644252.3	c.1499G>A	p.Gly500Asp	missense_variant	6/6		NM_013352.4	ENSP00000494147	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 13, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D;D;D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;.;D
M_CAP	Benign	0.030	D
MetaRNN	Pathogenic	0.83	D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.4	D;D;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;D;D
Vest4		0.89
MVP		0.70
MPC		1.0
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1554228151; hg19: chr6-116757130;