rs397515328

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_001382.4(DPAGT1):c.85A>T(p.Ile29Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000601 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

DPAGT1
NM_001382.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 7.67

Variant links:

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]

DPAGT1 links:

ENSG00000289124 (HGNC:):

ENSG00000289124 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 11-119101571-T-A is Pathogenic according to our data. Variant chr11-119101571-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65470.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DPAGT1	NM_001382.4 link	c.85A>T	p.Ile29Phe	missense_variant	Exon 1 of 9	ENST00000354202.9	NP_001373.2	Q9H3H5-1A0A024R3H8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DPAGT1	ENST00000354202.9 link	c.85A>T	p.Ile29Phe	missense_variant	Exon 1 of 9	1	NM_001382.4	ENSP00000346142.4		Q9H3H5-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152210

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:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000103

AC:

AN:

251472

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135920

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:

0.000849

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1461890

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

727246

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:

0.000835

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

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:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000602

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

DPAGT1-congenital disorder of glycosylation

Pathogenic:2

Aug 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jun 24, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous variant c.85A>T (p.Ile29Phe) has been observed in a proband with global developmental delay, microcephaly, central hypotonia, cortical blindness, camptodactyly, clinodactyly, MRI showed mild thinning of boady and splenium of corpus callosum, prominent bilateral lateral ventricles and fundus showed mild retinitis pigmentosa in a compound heterozygous state with the other variant c.160A>T (p.Ile54Phe). This variant is observed in 0.0103% gnomAD (aggregated) database (PM2_moderate). DPAGT1 has low rate of benign missense variants with 22 reported pathogenic missense variants (PP2_supporting). It has been previously reported PMID: 25500013 (PP5_supporting). This variant has been segregated in the parents. -

DPAGT1-congenital disorder of glycosylation;C3553645:Congenital myasthenic syndrome 13

Pathogenic:1

Aug 28, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Experimental studies have shown that this missense change affects DPAGT1 function (PMID: 25500013). This sequence change replaces isoleucine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 29 of the DPAGT1 protein (p.Ile29Phe). This variant is present in population databases (rs397515328, gnomAD 0.08%). This missense change has been observed in individuals with congenital disorder of glycosylation and/or congenital myasthenic syndrome (PMID: 23249953, 25500013; Invitae). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65470). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt DPAGT1 protein function. For these reasons, this variant has been classified as Pathogenic. -

Congenital myasthenic syndrome 13

Pathogenic:1

Jun 24, 2023

Institute of Medical Genetics and Genomics, Sir Ganga Ram Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The heterozygous variant c.85A>T (p.Ile29Phe) has been observed in a proband with motor developmental delay, frequent falls with gait abnormalities, myopathic facies, hypotonia and mild lordotic pressure in a compound heterozygous state with the other variant c.1139C>T (p.Thr380Ile). This variant is observed in 0.0103% gnomAD (aggregated) database (PM2_moderate). DPAGT1 has low rate of benign missense variants with 22 reported pathogenic missense variants (PP2_supporting). It has been previously reported PMID: 25500013 (PP5_supporting) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.68

BayesDel_addAF

Pathogenic

0.22

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.79

D;D;.

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.94

.;D;D

M_CAP

Pathogenic

0.75

MetaRNN

Uncertain

0.70

D;D;D

MetaSVM

Uncertain

0.72

MutationAssessor

Pathogenic

3.2

M;M;.

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.3

D;D;.

REVEL

Pathogenic

0.81

Sift

Benign

0.045

D;D;.

Sift4G

Uncertain

0.032

D;D;.

Polyphen

0.25

B;B;.

Vest4

0.97

MutPred

0.61

Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);Gain of loop (P = 0.0045);

MVP

0.99

MPC

1.3

ClinPred

0.73

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.86

gMVP

0.94

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