5-126555940-G-T

Position:

• chr5-126555940-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001182.5(ALDH7A1):​c.1084C>A​(p.Pro362Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.52

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.93

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.1084C>A	p.Pro362Thr	missense_variant	12/18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2	c.1000C>A	p.Pro334Thr	missense_variant	12/18		NP_001188306.1
ALDH7A1	NM_001202404.2	c.1008+3300C>A		intron_variant			NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.1084C>A	p.Pro362Thr	missense_variant	12/18	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyridoxine-dependent epilepsy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

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. 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 expected to disrupt ALDH7A1 protein function. ClinVar contains an entry for this variant (Variation ID: 1425446). This variant has not been reported in the literature in individuals affected with ALDH7A1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 362 of the ALDH7A1 protein (p.Pro362Thr). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T;D;.;T;.;.;T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.83	T;T;T;T;T;T;T
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Pathogenic	3.8	.;H;.;.;.;.;.
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-6.5	.;D;.;.;.;.;.
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0010	.;D;.;.;.;.;.
Sift4G	Pathogenic	0.0010	.;D;.;.;.;.;.
Polyphen		1.0	.;D;.;.;.;.;.
Vest4		0.96
MutPred		0.76		Loss of catalytic residue at W363 (P = 0.0487);Loss of catalytic residue at W363 (P = 0.0487);.;.;.;.;.;
MVP		0.91
MPC		0.66
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.97
gMVP		0.85

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-125891632;