rs375679649

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001382.4(DPAGT1):​c.125G>A​(p.Cys42Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000501 in 1,614,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00052 ( 0 hom. )

Consequence

DPAGT1
NM_001382.4 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:6

Conservation

PhyloP100: 0.764
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07133329).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
DPAGT1NM_001382.4 linkuse as main transcriptc.125G>A p.Cys42Tyr missense_variant 1/9 ENST00000354202.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
DPAGT1ENST00000354202.9 linkuse as main transcriptc.125G>A p.Cys42Tyr missense_variant 1/91 NM_001382.4 P1Q9H3H5-1
ENST00000686641.1 linkuse as main transcriptn.39C>T non_coding_transcript_exon_variant 1/1

Frequencies

GnomAD3 genomes
AF:
0.000328
AC:
50
AN:
152238
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000121
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000632
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000227
AC:
57
AN:
251356
Hom.:
0
AF XY:
0.000228
AC XY:
31
AN XY:
135890
show subpopulations
Gnomad AFR exome
AF:
0.0000616
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000416
Gnomad NFE exome
AF:
0.000413
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000519
AC:
759
AN:
1461852
Hom.:
0
Cov.:
31
AF XY:
0.000531
AC XY:
386
AN XY:
727224
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000431
Gnomad4 NFE exome
AF:
0.000643
Gnomad4 OTH exome
AF:
0.000331
GnomAD4 genome
AF:
0.000328
AC:
50
AN:
152238
Hom.:
0
Cov.:
32
AF XY:
0.000255
AC XY:
19
AN XY:
74380
show subpopulations
Gnomad4 AFR
AF:
0.000121
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.000632
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000458
Hom.:
0
Bravo
AF:
0.000344
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000247
AC:
30
EpiCase
AF:
0.000273
EpiControl
AF:
0.000474

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

DPAGT1-congenital disorder of glycosylation;C3553645:Congenital myasthenic syndrome 13 Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 14, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingInvitaeAug 23, 2022This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 42 of the DPAGT1 protein (p.Cys42Tyr). This variant is present in population databases (rs375679649, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with DPAGT1-related conditions. ClinVar contains an entry for this variant (Variation ID: 302751). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsSep 07, 2016- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 24, 2023The c.125G>A (p.C42Y) alteration is located in exon 1 (coding exon 1) of the DPAGT1 gene. This alteration results from a G to A substitution at nucleotide position 125, causing the cysteine (C) at amino acid position 42 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
DPAGT1-congenital disorder of glycosylation Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Pediatric Genomic Medicine, Children's Mercy Hospital and ClinicsSep 22, 2016- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
19
DANN
Benign
0.90
DEOGEN2
Benign
0.13
T;T;.
Eigen
Benign
-0.66
Eigen_PC
Benign
-0.40
FATHMM_MKL
Benign
0.21
N
LIST_S2
Uncertain
0.92
.;D;D
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.071
T;T;T
MetaSVM
Benign
-0.71
T
MutationAssessor
Benign
-0.54
N;N;.
MutationTaster
Benign
0.97
D;D;D
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
2.5
N;N;.
REVEL
Benign
0.27
Sift
Benign
1.0
T;T;.
Sift4G
Benign
1.0
T;T;.
Polyphen
0.0
B;B;.
Vest4
0.13
MVP
0.72
MPC
0.87
ClinPred
0.075
T
GERP RS
2.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.35
gMVP
0.65

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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.

Other links and lift over

dbSNP: rs375679649; hg19: chr11-118972241; API