chr5-126595120-C-T

Variant names:

• chr5-126595120-C-T
• rs1060502950
• NM_001182.5:c.79G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001182.5(ALDH7A1):​c.79G>A​(p.Ala27Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. A27P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.36
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.3451714).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.79G>A	p.Ala27Thr	missense_variant	Exon 1 of 18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001202404.2	c.79G>A	p.Ala27Thr	missense_variant	Exon 1 of 16		NP_001189333.2
ALDH7A1	NM_001201377.2	c.-6G>A		5_prime_UTR_variant	Exon 1 of 18		NP_001188306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.79G>A	p.Ala27Thr	missense_variant	Exon 1 of 18	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyridoxine-dependent epilepsy Uncertain:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.052	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.011	T;T;T;.;T;.;.;.;T;T;T;T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	T;T;T;T;T;T;T;T;T;T;T;T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.35	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.093	T
MutationAssessor	Uncertain	2.1	.;M;.;.;.;.;.;M;.;.;.;.
PhyloP100		2.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.49	.;N;.;.;.;.;.;N;.;.;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.28	.;T;.;.;.;.;.;T;.;.;T;T
Sift4G	Benign	0.47	.;T;.;.;.;.;.;T;.;T;.;.
Polyphen		0.38	.;B;.;.;.;.;.;.;.;.;.;.
Vest4		0.34, 0.44, 0.43
MutPred		0.38		Gain of phosphorylation at A27 (P = 0.0387);Gain of phosphorylation at A27 (P = 0.0387);Gain of phosphorylation at A27 (P = 0.0387);Gain of phosphorylation at A27 (P = 0.0387);Gain of phosphorylation at A27 (P = 0.0387);Gain of phosphorylation at A27 (P = 0.0387);Gain of phosphorylation at A27 (P = 0.0387);Gain of phosphorylation at A27 (P = 0.0387);Gain of phosphorylation at A27 (P = 0.0387);Gain of phosphorylation at A27 (P = 0.0387);.;Gain of phosphorylation at A27 (P = 0.0387);
MVP		0.87
MPC		0.19
ClinPred		0.86	D
GERP RS		5.0
PromoterAI		-0.23	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.087
gMVP		0.67
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1060502950; hg19: chr5-125930812;