1-63370989-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_013339.4(ALG6):​c.12G>A​(p.Trp4*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Consequence

ALG6
NM_013339.4 stop_gained

Scores

2
3
2

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.99
Variant links:
Genes affected
ALG6 (HGNC:23157): (ALG6 alpha-1,3-glucosyltransferase) This gene encodes a member of the ALG6/ALG8 glucosyltransferase family. The encoded protein catalyzes the addition of the first glucose residue to the growing lipid-linked oligosaccharide precursor of N-linked glycosylation. Mutations in this gene are associated with congenital disorders of glycosylation type Ic. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 73 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-63370989-G-A is Pathogenic according to our data. Variant chr1-63370989-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2861045.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ALG6NM_013339.4 linkc.12G>A p.Trp4* stop_gained Exon 2 of 15 ENST00000263440.6 NP_037471.2 Q9Y672

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ALG6ENST00000263440.6 linkc.12G>A p.Trp4* stop_gained Exon 2 of 15 5 NM_013339.4 ENSP00000263440.5 Q9Y672

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
32

ClinVar

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

Submissions by phenotype

ALG6-congenital disorder of glycosylation 1C Pathogenic:1
May 01, 2023
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. This sequence change creates a premature translational stop signal (p.Trp4*) in the ALG6 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALG6 are known to be pathogenic (PMID: 19862844). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with ALG6-related conditions. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.63
D
BayesDel_noAF
Pathogenic
0.29
CADD
Pathogenic
36
DANN
Uncertain
0.99
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Benign
0.64
D
Vest4
0.60
GERP RS
3.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-63836660; COSMIC: COSV99673504; API