3-184242643-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_005787.6(ALG3):​c.1188G>A​(p.Trp396*) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,412,942 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ALG3
NM_005787.6 stop_gained

Scores

4
2
1

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.87
Variant links:
Genes affected
ALG3 (HGNC:23056): (ALG3 alpha-1,3- mannosyltransferase) This gene encodes a member of the ALG3 family. The encoded protein catalyses the addition of the first dol-P-Man derived mannose in an alpha 1,3 linkage to Man5GlcNAc2-PP-Dol. Defects in this gene have been associated with congenital disorder of glycosylation type Id (CDG-Id) characterized by abnormal N-glycosylation. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0979 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 3-184242643-C-T is Pathogenic according to our data. Variant chr3-184242643-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2780035.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALG3NM_005787.6 linkc.1188G>A p.Trp396* stop_gained Exon 9 of 9 ENST00000397676.8 NP_005778.1 Q92685-1
ALG3NM_001006941.2 linkc.1044G>A p.Trp348* stop_gained Exon 9 of 9 NP_001006942.1 Q92685-2
ALG3NR_024533.1 linkn.1119G>A non_coding_transcript_exon_variant Exon 8 of 8
ALG3NR_024534.1 linkn.1182G>A non_coding_transcript_exon_variant Exon 9 of 9

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALG3ENST00000397676.8 linkc.1188G>A p.Trp396* stop_gained Exon 9 of 9 1 NM_005787.6 ENSP00000380793.3 Q92685-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000212
AC:
3
AN:
1412942
Hom.:
0
Cov.:
32
AF XY:
0.00000287
AC XY:
2
AN XY:
696092
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000510
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.0000151

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

ALG3-congenital disorder of glycosylation Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpApr 22, 2024This sequence change creates a premature translational stop signal (p.Trp396*) in the ALG3 gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 43 amino acid(s) of the ALG3 protein. This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with congenital disorder of glycosylation (PMID: 33187827). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts a region of the ALG3 protein in which other variant(s) (p.Trp421*) have been determined to be pathogenic (PMID: 31067009). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.57
D
BayesDel_noAF
Pathogenic
0.59
CADD
Pathogenic
44
DANN
Uncertain
0.99
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Uncertain
0.96
D
Vest4
0.82
ClinPred
1.0
D
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.20
Position offset: -27

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: rs1287098925; hg19: chr3-183960431; API