5-126561094-T-A
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_001182.5(ALDH7A1):c.902A>T(p.Asn301Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000022 ( 0 hom. )
Consequence
ALDH7A1
NM_001182.5 missense
NM_001182.5 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 5.93
Genes affected
ALDH7A1 (HGNC:877): (aldehyde dehydrogenase 7 family member A1) The protein encoded by this gene is a member of subfamily 7 in the aldehyde dehydrogenase gene family. These enzymes are thought to play a major role in the detoxification of aldehydes generated by alcohol metabolism and lipid peroxidation. This particular member has homology to a previously described protein from the green garden pea, the 26g pea turgor protein. It is also involved in lysine catabolism that is known to occur in the mitochondrial matrix. Recent reports show that this protein is found both in the cytosol and the mitochondria, and the two forms likely arise from the use of alternative translation initiation sites. An additional variant encoding a different isoform has also been found for this gene. Mutations in this gene are associated with pyridoxine-dependent epilepsy. Several related pseudogenes have also been identified. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.976
PP5
Variant 5-126561094-T-A is Pathogenic according to our data. Variant chr5-126561094-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126561094-T-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALDH7A1 | NM_001182.5 | c.902A>T | p.Asn301Ile | missense_variant | 10/18 | ENST00000409134.8 | NP_001173.2 | |
ALDH7A1 | NM_001201377.2 | c.818A>T | p.Asn273Ile | missense_variant | 10/18 | NP_001188306.1 | ||
ALDH7A1 | NM_001202404.2 | c.902A>T | p.Asn301Ile | missense_variant | 10/16 | NP_001189333.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALDH7A1 | ENST00000409134.8 | c.902A>T | p.Asn301Ile | missense_variant | 10/18 | 1 | NM_001182.5 | ENSP00000387123.3 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251328Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135834
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GnomAD4 exome AF: 0.0000219 AC: 32AN: 1460948Hom.: 0 Cov.: 30 AF XY: 0.0000179 AC XY: 13AN XY: 726704
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74484
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pyridoxine-dependent epilepsy Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Feb 04, 2023 | This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 301 of the ALDH7A1 protein (p.Asn301Ile). This variant is present in population databases (rs121912711, gnomAD 0.004%). This missense change has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 17068770, 20554659, 24664145). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Asn273Ile. ClinVar contains an entry for this variant (Variation ID: 18001). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALDH7A1 protein function. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 22784480). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2007 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust | Aug 26, 2021 | Criteria Codes: PS3_Supp PM2 PM3_Str PP3 - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 28, 2023 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 13, 2022 | Published functional studies did not demonstrate detectable enzymatic activity (Coulter-Mackie et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25553455, 27342130, 30005813, 24664145, 17068770, 26555630, 23022070, 31737911, 30043187, 32956737, 22784480) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
T;D;T;.;T;.;.;.;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;H;.;.;.;.;.;H;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
.;D;.;.;.;.;.;D;.
REVEL
Pathogenic
Sift
Pathogenic
.;D;.;.;.;.;.;D;.
Sift4G
Pathogenic
.;D;.;.;.;.;.;D;.
Polyphen
1.0
.;D;.;.;.;.;.;.;.
Vest4
0.90, 0.93
MutPred
Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);.;
MVP
0.98
MPC
0.73
ClinPred
D
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