rs147471420
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Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 2P and 8B. PM2BP4_ModerateBP6BP7BS1
The NM_003748.4(ALDH4A1):c.1098G>A(p.Gly366=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00054 in 1,593,538 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.00044 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00055 ( 1 hom. )
Consequence
ALDH4A1
NM_003748.4 synonymous
NM_003748.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 1.27
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 Likely_benign. Variant got -6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.24).
BP6
Variant 1-18877455-C-T is Benign according to our data. Variant chr1-18877455-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 294378.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
BP7
Synonymous conserved (PhyloP=1.27 with no splicing effect.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00044 (67/152372) while in subpopulation AMR AF= 0.000914 (14/15310). AF 95% confidence interval is 0.000552. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
|---|---|---|---|---|---|---|---|
| ALDH4A1 | NM_003748.4 | c.1098G>A | p.Gly366= | synonymous_variant | 10/15 | ENST00000375341.8 | |
| ALDH4A1 | NM_170726.3 | c.1098G>A | p.Gly366= | synonymous_variant | 10/16 | ||
| ALDH4A1 | NM_001319218.2 | c.1098G>A | p.Gly366= | synonymous_variant | 10/14 | ||
| ALDH4A1 | NM_001161504.2 | c.918G>A | p.Gly306= | synonymous_variant | 10/15 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| ALDH4A1 | ENST00000375341.8 | c.1098G>A | p.Gly366= | synonymous_variant | 10/15 | 1 | NM_003748.4 | P1 | |
| ALDH4A1 | ENST00000290597.9 | c.1098G>A | p.Gly366= | synonymous_variant | 10/16 | 1 | P1 | ||
| ALDH4A1 | ENST00000538839.5 | c.1098G>A | p.Gly366= | synonymous_variant | 10/14 | 1 | |||
| ALDH4A1 | ENST00000538309.5 | c.918G>A | p.Gly306= | synonymous_variant | 10/15 | 2 |
Frequencies
GnomAD3 genomes 0.000447 AC: 68AN: 152254Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000625 AC: 136AN: 217748Hom.: 0 AF XY: 0.000569 AC XY: 67AN XY: 117658
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GnomAD4 exome AF: 0.000551 AC: 794AN: 1441166Hom.: 1 Cov.: 33 AF XY: 0.000515 AC XY: 368AN XY: 714972
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GnomAD4 genome 0.000440 AC: 67AN: 152372Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36AN XY: 74500
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hyperprolinemia type 2 Uncertain:1Benign:1
| Benign, criteria provided, single submitter | clinical testing | Invitae | Dec 07, 2023 | - - |
| Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 13, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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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