rs398123609

Positions:

• chr11-119100774-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Strong

The ENST00000354202.9(DPAGT1):​c.352C>G​(p.Leu118Val) variant causes a missense change. 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: DPAGT1 ENST00000354202.9 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.92

Genes affected

DPAGT1 (HGNC:2995): (dolichyl-phosphate N-acetylglucosaminephosphotransferase 1) The protein encoded by this gene is an enzyme that catalyzes the first step in the dolichol-linked oligosaccharide pathway for glycoprotein biosynthesis. This enzyme belongs to the glycosyltransferase family 4. This protein is an integral membrane protein of the endoplasmic reticulum. The congenital disorder of glycosylation type Ij is caused by mutation in the gene encoding this enzyme. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in ENST00000354202.9
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPAGT1	NM_001382.4	c.352C>G	p.Leu118Val	missense_variant	3/9	ENST00000354202.9	NP_001373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPAGT1	ENST00000354202.9	c.352C>G	p.Leu118Val	missense_variant	3/9	1	NM_001382.4	ENSP00000346142	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

DPAGT1-congenital disorder of glycosylation Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Sep 01, 2017

Likely pathogenicity based on finding it once in our laboratory in a homozygous state in a 1-month-old female with IUGR, abnormal movements, dysmorphisms, contractures, structural brain abnormalities, eye anomalies, skeletal abnormalities, limb malformations. Biochemical studies consistent with disorder of glycosylation -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 31, 2012

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.58	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.8	D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.99	D;D
Vest4		0.93
MutPred		0.79		Gain of methylation at R123 (P = 0.1287);Gain of methylation at R123 (P = 0.1287);
MVP		0.98
MPC		1.4
ClinPred		0.98	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.87
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.50		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.50		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs398123609; hg19: chr11-118971484;