rs779536510
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_ModeratePM2PP5_Very_Strong
The NM_003748.4(ALDH4A1):c.1560_1561insT(p.Gly521TrpfsTer10) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
ALDH4A1
NM_003748.4 frameshift
NM_003748.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: -1.33
Genes affected
ALDH4A1 (HGNC:406): (aldehyde dehydrogenase 4 family member A1) This protein belongs to the aldehyde dehydrogenase family of proteins. This enzyme is a mitochondrial matrix NAD-dependent dehydrogenase which catalyzes the second step of the proline degradation pathway, converting pyrroline-5-carboxylate to glutamate. Deficiency of this enzyme is associated with type II hyperprolinemia, an autosomal recessive disorder characterized by accumulation of delta-1-pyrroline-5-carboxylate (P5C) and proline. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. [provided by RefSeq, Jun 2009]
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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 is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.078 CDS is truncated, and there are 2 pathogenic variants in the truncated region.
PM2
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Very rare variant in population databases, with high coverage;
PP5
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Variant 1-18874481-C-CA is Pathogenic according to our data. Variant chr1-18874481-C-CA is described in ClinVar as [Likely_pathogenic]. Clinvar id is 4002.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH4A1 | NM_003748.4 | c.1560_1561insT | p.Gly521TrpfsTer10 | frameshift_variant | 14/15 | ENST00000375341.8 | |
ALDH4A1 | NM_001161504.2 | c.1380_1381insT | p.Gly461TrpfsTer10 | frameshift_variant | 14/15 | ||
ALDH4A1 | NM_001319218.2 | c.1407_1408insT | p.Gly470TrpfsTer10 | frameshift_variant | 13/14 | ||
ALDH4A1 | NM_170726.3 | c.1560_1561insT | p.Gly521TrpfsTer10 | frameshift_variant | 14/16 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH4A1 | ENST00000375341.8 | c.1560_1561insT | p.Gly521TrpfsTer10 | frameshift_variant | 14/15 | 1 | NM_003748.4 | P1 | |
ALDH4A1 | ENST00000290597.9 | c.1560_1561insT | p.Gly521TrpfsTer10 | frameshift_variant | 14/16 | 1 | P1 | ||
ALDH4A1 | ENST00000538839.5 | c.1407_1408insT | p.Gly470TrpfsTer10 | frameshift_variant | 13/14 | 1 | |||
ALDH4A1 | ENST00000538309.5 | c.1380_1381insT | p.Gly461TrpfsTer10 | frameshift_variant | 14/15 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 34
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GnomAD3 exomes AF: 0.0000120 AC: 3AN: 250726Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135540
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GnomAD4 exome AF: 0.0000205 AC: 30AN: 1461764Hom.: 0 Cov.: 32 AF XY: 0.0000234 AC XY: 17AN XY: 727186
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152204Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0AN XY: 74350
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hyperprolinemia type 2 Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 22, 2024 | Variant summary: ALDH4A1 c.1560dupT (p.Gly521TrpfsX10) results in a premature termination codon, predicted to cause a truncation of the encoded protein, which is a commonly known mechanism for disease. The variant allele was found at a frequency of 1.2e-05 in 250726 control chromosomes. c.1560dupT has been reported in the literature in the homozygous state in multiple members of a family affected with hyperprolinemia type II (Geraghty_1998). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function (Geraghty_1998). The variant was determined to result in an absence of growth on proline and absent enzymatic activity compared to wild-type in a yeast expression assay. The following publication has been ascertained in the context of this evaluation (PMID: 9700195). ClinVar contains an entry for this variant (Variation ID: 4002). Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Sep 01, 1998 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Mar 30, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2022 | ALDH4A1: PP1:Strong, PVS1:Strong, PM2, PM3, PS3:Supporting - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 23, 2022 | Published functional studies demonstrate a damaging effect as the variant abolished P5CDh activity in yeast cells (Geraghty et al., 1998); Not observed at significant frequency in large population cohorts (gnomAD); Frameshift variant predicted to result in protein truncation, as the last 43 amino acids are replaced with 9 different amino acids in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 9700195) - |
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