chr5-126595080-G-C

Variant names:

• chr5-126595080-G-C
• rs745385277
• NM_001182.5:c.119C>G

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_001182.5(ALDH7A1):​c.119C>G​(p.Ala40Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000688 in 1,453,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A40V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 4.21
• Publications: 1 publications found

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]

ALDH7A1 Gene-Disease associations (from GenCC):

• pyridoxine-dependent epilepsy

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Illumina, Orphanet, ClinGen
• pyridoxine-dependent epilepsy caused by ALDH7A1 mutant

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 0.36846 (below the threshold of 3.09). Trascript score misZ: 0.93117 (below the threshold of 3.09). GenCC associations: The gene is linked to pyridoxine-dependent epilepsy, pyridoxine-dependent epilepsy caused by ALDH7A1 mutant.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22326162).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.119C>G	p.Ala40Gly	missense_variant	Exon 1 of 18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2	c.35C>G	p.Ala12Gly	missense_variant	Exon 1 of 18		NP_001188306.1
ALDH7A1	NM_001202404.2	c.119C>G	p.Ala40Gly	missense_variant	Exon 1 of 16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.119C>G	p.Ala40Gly	missense_variant	Exon 1 of 18	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1453458 Hom.: 0 Cov.: 32 AF XY: 0.00000969 AC XY: 7 AN XY: 722180

African (AFR) AF: 0.00 AC: 0 AN: 33166

American (AMR) AF: 0.00 AC: 0 AN: 43932

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25898

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.00 AC: 0 AN: 84440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52782

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108114

Other (OTH) AF: 0.000166 AC: 10 AN: 60068

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyridoxine-dependent epilepsy Uncertain:2

Apr 11, 2023

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 40 of the ALDH7A1 protein (p.Ala40Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 30043187). ClinVar contains an entry for this variant (Variation ID: 569552). 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 not expected to disrupt ALDH7A1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Inborn genetic diseases Uncertain:1

Jun 30, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.A40G variant (also known as c.119C>G), located in coding exon 1 of the ALDH7A1 gene, results from a C to G substitution at nucleotide position 119. The alanine at codon 40 is replaced by glycine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T;T;T;.;T;.;.;.;T;T;T;T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.90	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.0	.;L;.;.;.;.;.;L;.;.;.;.
PhyloP100		4.2
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.45	.;N;.;.;.;.;.;N;.;.;N;N
REVEL	Benign	0.13
Sift	Benign	0.37	.;T;.;.;.;.;.;T;.;.;T;T
Sift4G	Benign	0.51	.;T;.;.;.;.;.;T;.;T;.;.
Polyphen		0.0	.;B;.;.;.;.;.;.;.;.;.;.
Vest4		0.17, 0.20, 0.23
MutPred		0.40		Loss of catalytic residue at A40 (P = 0.034);Loss of catalytic residue at A40 (P = 0.034);Loss of catalytic residue at A40 (P = 0.034);Loss of catalytic residue at A40 (P = 0.034);Loss of catalytic residue at A40 (P = 0.034);Loss of catalytic residue at A40 (P = 0.034);Loss of catalytic residue at A40 (P = 0.034);Loss of catalytic residue at A40 (P = 0.034);Loss of catalytic residue at A40 (P = 0.034);Loss of catalytic residue at A40 (P = 0.034);.;Loss of catalytic residue at A40 (P = 0.034);
MVP		0.83
MPC		0.15
ClinPred		0.50	T
GERP RS		4.2
PromoterAI		-0.14	Neutral
Varity_R		0.22
gMVP		0.55
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs745385277; hg19: chr5-125930772;