rs138544311

Positions:

chr11-119097475-A-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The ENST00000354202.9(DPAGT1):c.994T>G(p.Phe332Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,614,186 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 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 0.0017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0020 ( 2 hom. )

Consequence

DPAGT1
ENST00000354202.9 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:4O:1

Conservation

PhyloP100: 1.73

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01094988).

BP6

Variant 11-119097475-A-C is Benign according to our data. Variant chr11-119097475-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167007.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=5, not_provided=1}.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00165 (252/152304) while in subpopulation AMR AF= 0.00503 (77/15300). AF 95% confidence interval is 0.00413. There are 0 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DPAGT1	NM_001382.4 linkuse as main transcript	c.994T>G	p.Phe332Val	missense_variant	7/9	ENST00000354202.9	NP_001373.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DPAGT1	ENST00000354202.9 linkuse as main transcript	c.994T>G	p.Phe332Val	missense_variant	7/9	1	NM_001382.4	ENSP00000346142	P1	Q9H3H5-1

Frequencies

GnomAD3 genomes

AF:

0.00166

AC:

252

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00504

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000283

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00212

Gnomad OTH

AF:

0.00144

GnomAD3 exomes

AF:

0.00120

AC:

302

AN:

251490

Hom.:

AF XY:

0.00116

AC XY:

158

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.000694

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00189

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.00197

AC:

2881

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

1420

AN XY:

727242

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.00170

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000197

Gnomad4 FIN exome

AF:

0.000468

Gnomad4 NFE exome

AF:

0.00238

Gnomad4 OTH exome

AF:

0.00151

GnomAD4 genome

AF:

0.00165

AC:

252

AN:

152304

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00503

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.000283

Gnomad4 NFE

AF:

0.00212

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00195

Hom.:

Bravo

AF:

0.00175

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00233

AC:

ExAC

AF:

0.00109

AC:

132

EpiCase

AF:

0.00267

EpiControl

AF:

0.00249

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:4Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2023	Reported in an individual referred for testing for congenital disorders of glycosylation in published literature; however, additional information on clinical presentation, segregation, and co-occurrence with other variants was not provided (Jones et al., 2013); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23806237, 31824661, 36094697) -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 28, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	DPAGT1: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2021	- -

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

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	Variant interpretted as Uncertain significance and reported on 12/09/2017 by GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

DPAGT1-congenital disorder of glycosylation

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

DPAGT1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 05, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Acute intermittent porphyria

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.12

T;T;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.034

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.90

.;D;D

M_CAP

Benign

0.035

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

-0.20

N;N;.

MutationTaster

Benign

0.82

D;D;D

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.21

N;N;.

REVEL

Benign

0.27

Sift

Benign

0.30

T;T;.

Sift4G

Benign

0.31

T;T;.

Polyphen

0.0

B;B;.

Vest4

0.33

MVP

0.93

MPC

0.68

ClinPred

0.016

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.72

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