rs759244819
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_024105.4(ALG12):c.1001del(p.Asn334ThrfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000204 in 1,614,008 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000020 ( 0 hom. )
Consequence
ALG12
NM_024105.4 frameshift
NM_024105.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 3.30
Genes affected
ALG12 (HGNC:19358): (ALG12 alpha-1,6-mannosyltransferase) This gene encodes a member of the glycosyltransferase 22 family. The encoded protein catalyzes the addition of the eighth mannose residue in an alpha-1,6 linkage onto the dolichol-PP-oligosaccharide precursor (dolichol-PP-Man(7)GlcNAc(2)) required for protein glycosylation. Mutations in this gene have been associated with congenital disorder of glycosylation type Ig (CDG-Ig)characterized by abnormal N-glycosylation. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
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Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 22-49904497-GT-G is Pathogenic according to our data. Variant chr22-49904497-GT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 242854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALG12 | NM_024105.4 | c.1001del | p.Asn334ThrfsTer15 | frameshift_variant | 8/10 | ENST00000330817.11 | |
ALG12 | XM_017028936.2 | c.1001del | p.Asn334ThrfsTer15 | frameshift_variant | 8/10 | ||
ALG12 | XM_017028937.2 | c.1001del | p.Asn334ThrfsTer15 | frameshift_variant | 8/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALG12 | ENST00000330817.11 | c.1001del | p.Asn334ThrfsTer15 | frameshift_variant | 8/10 | 1 | NM_024105.4 | P1 | |
ENST00000610245.1 | n.2272del | non_coding_transcript_exon_variant | 1/1 | ||||||
ALG12 | ENST00000486602.1 | c.207del | p.Asn70ThrfsTer15 | frameshift_variant | 2/4 | 3 | |||
ALG12 | ENST00000492791.1 | c.524-114del | intron_variant, NMD_transcript_variant | 3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152130Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000518 AC: 13AN: 251142Hom.: 0 AF XY: 0.0000368 AC XY: 5AN XY: 135894
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GnomAD4 exome AF: 0.0000198 AC: 29AN: 1461878Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13AN XY: 727242
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
ALG12-congenital disorder of glycosylation Pathogenic:6
Pathogenic, no assertion criteria provided | literature only | OMIM | May 21, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | Apr 01, 2014 | This variant was found in trans with pathogenic variant NM_024105.3:c.117delG in an individual with congenital disorder of glycosylation type Ig. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Feb 06, 2020 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | Nov 07, 2019 | This frameshifting variant in exon 8 of 10 introduces a premature stop codon and is therefore predicted to result in loss of normal protein function. This variant has been previously reported as a compound heterozygous change in patients with Congenital disorder of glycosylation type Ig (PMID: 25019053). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0052% (13/251142) and thus is presumed to be rare. Based on the available evidence, the c.1001del (p.Asn334ThrfsTer15) variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change creates a premature translational stop signal (p.Asn334Thrfs*15) in the ALG12 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ALG12 are known to be pathogenic (PMID: 15639192, 31481313). This variant is present in population databases (rs759244819, gnomAD 0.02%). This premature translational stop signal has been observed in individual(s) with clinical features of congenital disorders of glycosylation (PMID: 25019053, 31481313). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 242854). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 27, 2024 | Variant summary: ALG12 c.1001delA (p.Asn334ThrfsX15) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 5.2e-05 in 251142 control chromosomes. c.1001delA has been reported in the literature in individuals affected with ALG12-Congenital Disorder Of Glycosylation (e.g. Murali_2014). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 25019053). ClinVar contains an entry for this variant (Variation ID: 242854). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 23, 2020 | The alteration results in a premature stop codon: _x000D_ _x000D_ The c.1001delA (p.N334Tfs*15) alteration, located in exon 8 (coding exon 7) of the ALG12 gene, results from a deletion of one nucleotide at position 1001, causing a translational frameshift with a predicted alternate stop codon after 15 amino acids. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. The alteration is rare in population databases:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD) database, the ALG12 c.1001delA alteration was observed in <0.01% (13/251142) of total alleles studied, with a frequency of 0.03% (9/34584) in the Latino subpopulation. The alteration has been observed in affected individuals: _x000D_ _x000D_ This alteration was reported with another frameshift alteration, c.117delG (p.Q40Rfs*34), in ALG12 in an infant with rhizomelic short stature, talipes equinovarus, platyspondyly, and joint dislocations (Murali, 2014). Tahata, et al. (2019) reported this alteration in trans with c.671C>T (p.T224M) in two affected brothers who only had cognitive impairment and coagulation defects. They also had a younger brother who died from a severe multisystem disease at age 18 months and was suspected of having congenital disorder of glycosylation. Based on the available evidence, this alteration is classified as pathogenic. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 24, 2023 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 31589614, 31481313, 33144682, 25019053, 33413482) - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at