chr1-18874481-C-CA
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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):βc.1560_1561insTβ(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 (β β ).
Frequency
Genomes: π 0.0000066 ( 0 hom., cov: 34)
Exomes π: 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
Very rare variant in population databases, with high coverage;
PP5
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 |
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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