chr5-126595045-C-G

Position:

• chr5-126595045-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001182.5(ALDH7A1):​c.154G>C​(p.Glu52Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000618 in 1,457,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 3.81

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11964071).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.154G>C	p.Glu52Gln	missense_variant	1/18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2	c.70G>C	p.Glu24Gln	missense_variant	1/18		NP_001188306.1
ALDH7A1	NM_001202404.2	c.154G>C	p.Glu52Gln	missense_variant	1/16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.154G>C	p.Glu52Gln	missense_variant	1/18	1	NM_001182.5	ENSP00000387123	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000370 AC: 9 AN: 243176 Hom.: 0 AF XY: 0.0000304 AC XY: 4 AN XY: 131620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000264

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000618 AC: 9 AN: 1457380 Hom.: 0 Cov.: 32 AF XY: 0.00000552 AC XY: 4 AN XY: 724534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000203

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Bravo AF: 0.0000151

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyridoxine-dependent epilepsy Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2022	This sequence change replaces glutamic acid, which is acidic and polar, with glutamine, which is neutral and polar, at codon 52 of the ALDH7A1 protein (p.Glu52Gln). This variant is present in population databases (rs765562932, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with ALDH7A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 465324). 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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 06, 2020

The c.154G>C (p.E52Q) alteration is located in exon 1 (coding exon 1) of the ALDH7A1 gene. This alteration results from a G to C substitution at nucleotide position 154, causing the glutamic acid (E) at amino acid position 52 to be replaced by a glutamine (Q). Based on data from the Genome Aggregation Database (gnomAD) database, the ALDH7A1 c.154G>C alteration was observed in <0.01% (9/243176) of total alleles studied, with a frequency of 0.03% (9/34050) in the Latino subpopulation. This amino acid position is not well conserved in available vertebrate species. The p.E52Q alteration is predicted to be tolerated by in silico analysis. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 30, 2022

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0068	T;T;T;.;T;.;.;.;T;T;T;T
Eigen	Benign	-0.092
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.6	.;L;.;.;.;.;.;L;.;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.010	.;N;.;.;.;.;.;N;.;.;N;N
REVEL	Benign	0.21
Sift	Benign	0.38	.;T;.;.;.;.;.;T;.;.;T;T
Sift4G	Benign	0.61	.;T;.;.;.;.;.;T;.;T;.;.
Polyphen		0.015	.;B;.;.;.;.;.;.;.;.;.;.
Vest4		0.22, 0.29, 0.32
MutPred		0.36		Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);Loss of sheet (P = 0.0817);.;Loss of sheet (P = 0.0817);
MVP		0.80
MPC		0.15
ClinPred		0.17	T
GERP RS		5.0
Varity_R		0.41
gMVP		0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs765562932; hg19: chr5-125930737;