3-184242643-C-T
Variant names:
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
NM_005787.6 stop_gained
Scores
4
2
1
Clinical Significance
Conservation
PhyloP100: 7.87
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 |
---|---|---|---|---|---|---|---|---|
ALG3 | NM_005787.6 | c.1188G>A | p.Trp396* | stop_gained | Exon 9 of 9 | ENST00000397676.8 | NP_005778.1 | |
ALG3 | NM_001006941.2 | c.1044G>A | p.Trp348* | stop_gained | Exon 9 of 9 | NP_001006942.1 | ||
ALG3 | NR_024533.1 | n.1119G>A | non_coding_transcript_exon_variant | Exon 8 of 8 | ||||
ALG3 | NR_024534.1 | n.1182G>A | non_coding_transcript_exon_variant | Exon 9 of 9 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD4 exome AF: 0.00000212 AC: 3AN: 1412942Hom.: 0 Cov.: 32 AF XY: 0.00000287 AC XY: 2AN XY: 696092
GnomAD4 exome
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3
AN:
1412942
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32
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2
AN XY:
696092
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
Bravo
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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 submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 22, 2024 | This 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:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
Vest4
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -27
Find out detailed SpliceAI scores and Pangolin per-transcript scores at