rs6695033
Positions:
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_003748.4(ALDH4A1):āc.1417A>Gā(p.Thr473Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0282 in 1,614,048 control chromosomes in the GnomAD database, including 1,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (ā ā ).
Frequency
Genomes: š 0.062 ( 588 hom., cov: 33)
Exomes š: 0.025 ( 915 hom. )
Consequence
ALDH4A1
NM_003748.4 missense
NM_003748.4 missense
Scores
4
13
Clinical Significance
Conservation
PhyloP100: 4.54
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 Benign. Variant got -20 ACMG points.
BP4
?
Computational evidence support a benign effect (MetaRNN=0.0016415417).
BP6
?
Variant 1-18875425-T-C is Benign according to our data. Variant chr1-18875425-T-C is described in ClinVar as [Benign]. Clinvar id is 294366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-18875425-T-C is described in Lovd as [Likely_benign].
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH4A1 | NM_003748.4 | c.1417A>G | p.Thr473Ala | missense_variant | 13/15 | ENST00000375341.8 | |
ALDH4A1 | NM_170726.3 | c.1417A>G | p.Thr473Ala | missense_variant | 13/16 | ||
ALDH4A1 | NM_001319218.2 | c.1264A>G | p.Thr422Ala | missense_variant | 12/14 | ||
ALDH4A1 | NM_001161504.2 | c.1237A>G | p.Thr413Ala | missense_variant | 13/15 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH4A1 | ENST00000375341.8 | c.1417A>G | p.Thr473Ala | missense_variant | 13/15 | 1 | NM_003748.4 | P1 | |
ALDH4A1 | ENST00000290597.9 | c.1417A>G | p.Thr473Ala | missense_variant | 13/16 | 1 | P1 | ||
ALDH4A1 | ENST00000538839.5 | c.1264A>G | p.Thr422Ala | missense_variant | 12/14 | 1 | |||
ALDH4A1 | ENST00000538309.5 | c.1237A>G | p.Thr413Ala | missense_variant | 13/15 | 2 |
Frequencies
GnomAD3 genomes ? AF: 0.0617 AC: 9375AN: 152066Hom.: 586 Cov.: 33
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GnomAD3 exomes AF: 0.0310 AC: 7787AN: 251476Hom.: 316 AF XY: 0.0287 AC XY: 3906AN XY: 135918
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GnomAD4 exome AF: 0.0247 AC: 36180AN: 1461864Hom.: 915 Cov.: 31 AF XY: 0.0243 AC XY: 17647AN XY: 727240
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GnomAD4 genome ? AF: 0.0617 AC: 9392AN: 152184Hom.: 588 Cov.: 33 AF XY: 0.0595 AC XY: 4428AN XY: 74414
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102
ESP6500AA
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687
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ClinVar
Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hyperprolinemia type 2 Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.;T;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;M;.
MutationTaster
Benign
P;P;P;P
PrimateAI
Benign
T
PROVEAN
Uncertain
D;N;D;D
REVEL
Benign
Sift
Benign
T;T;T;T
Sift4G
Benign
T;T;T;T
Polyphen
B;.;B;.
Vest4
MPC
0.35
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
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