5-126595045-C-T

Variant names:

• chr5-126595045-C-T
• rs765562932
• NM_001182.5:c.154G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001182.5(ALDH7A1):​c.154G>A​(p.Glu52Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,457,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E52Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.81
• 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: Orphanet, Illumina, ClinGen
• pyridoxine-dependent epilepsy caused by ALDH7A1 mutant

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 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=0.19151998).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001182.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH7A1	NM_001182.5	MANE Select	c.154G>A	p.Glu52Lys	missense	Exon 1 of 18	NP_001173.2	P49419-1
	ALDH7A1	NM_001201377.2		c.70G>A	p.Glu24Lys	missense	Exon 1 of 18	NP_001188306.1	P49419-2
	ALDH7A1	NM_001202404.2		c.154G>A	p.Glu52Lys	missense	Exon 1 of 16	NP_001189333.2	P49419-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH7A1	ENST00000409134.8	TSL:1 MANE Select	c.154G>A	p.Glu52Lys	missense	Exon 1 of 18	ENSP00000387123.3	P49419-1
	ALDH7A1	ENST00000636879.1	TSL:5	c.154G>A	p.Glu52Lys	missense	Exon 1 of 19	ENSP00000490811.1	A0A1B0GW77
	ALDH7A1	ENST00000939100.1		c.154G>A	p.Glu52Lys	missense	Exon 1 of 19	ENSP00000609159.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1457380 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 724534

African (AFR) AF: 0.00 AC: 0 AN: 33322

American (AMR) AF: 0.00 AC: 0 AN: 44384

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39508

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85130

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5446

European-Non Finnish (NFE) AF: 9.01e-7 AC: 1 AN: 1110314

Other (OTH) AF: 0.00 AC: 0 AN: 60206

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0051	T
Eigen	Benign	-0.20
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	1.6	L
PhyloP100		3.8
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.27	N
REVEL	Uncertain	0.32
Sift	Benign	0.49	T
Sift4G	Benign	0.84	T
Polyphen		0.0020	B
Vest4		0.34
MutPred		0.44		Gain of ubiquitination at E52 (P = 0.0094)
MVP		0.81
MPC		0.17
ClinPred		0.86	D
GERP RS		5.0
PromoterAI		-0.0064	Neutral
Varity_R		0.49
gMVP		0.65
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs765562932; hg19: chr5-125930737;