rs1060499755
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong
The NM_001182.5(ALDH7A1):āc.571A>Gā(p.Ile191Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,894 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 (ā ā ).
Frequency
Genomes: not found (cov: 31)
Exomes š: 6.8e-7 ( 0 hom. )
Consequence
ALDH7A1
NM_001182.5 missense
NM_001182.5 missense
Scores
7
8
4
Clinical Significance
Conservation
PhyloP100: 7.74
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 12 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.85
PP5
Variant 5-126577158-T-C is Pathogenic according to our data. Variant chr5-126577158-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 402176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126577158-T-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ALDH7A1 | NM_001182.5 | c.571A>G | p.Ile191Val | missense_variant | 6/18 | ENST00000409134.8 | NP_001173.2 | |
ALDH7A1 | NM_001201377.2 | c.487A>G | p.Ile163Val | missense_variant | 6/18 | NP_001188306.1 | ||
ALDH7A1 | NM_001202404.2 | c.571A>G | p.Ile191Val | missense_variant | 6/16 | NP_001189333.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ALDH7A1 | ENST00000409134.8 | c.571A>G | p.Ile191Val | missense_variant | 6/18 | 1 | NM_001182.5 | ENSP00000387123.3 |
Frequencies
GnomAD3 genomes Cov.: 31
GnomAD3 genomes
Cov.:
31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461894Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727248
GnomAD4 exome
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1
AN:
1461894
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Cov.:
31
AF XY:
AC XY:
1
AN XY:
727248
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 31
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Abnormal brain morphology Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine | - | - - |
Pyridoxine-dependent epilepsy Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Aug 23, 2024 | Variant summary: ALDH7A1 c.571A>G (p.Ile191Val) results in a conservative amino acid change located in the Aldehyde dehydrogenase domain (IPR015590) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251476 control chromosomes. c.571A>G has been reported in the literature in a setting of whole exome sequencing in homozygous individuals affected with clinical features of Pyridoxine-Dependent Epilepsy (e.g. Karaca_2015). These data indicate that the variant is likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 26539891). ClinVar contains an entry for this variant (Variation ID: 402176). Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.;T;.;.;.;T;T;T;T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;.;.;.;.;.;M;.;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;.;.;.;.;.;N;.;.;N;.
REVEL
Pathogenic
Sift
Uncertain
.;D;.;.;.;.;.;T;.;.;D;.
Sift4G
Uncertain
.;D;.;.;.;.;.;D;.;D;.;.
Polyphen
1.0
.;D;.;.;.;.;.;.;.;.;.;.
Vest4
0.87, 0.85, 0.89
MutPred
Gain of catalytic residue at I191 (P = 0.2456);Gain of catalytic residue at I191 (P = 0.2456);Gain of catalytic residue at I191 (P = 0.2456);Gain of catalytic residue at I191 (P = 0.2456);.;.;.;Gain of catalytic residue at I191 (P = 0.2456);.;Gain of catalytic residue at I191 (P = 0.2456);.;.;
MVP
0.93
MPC
0.57
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at