rs796052269

Positions:

• chr5-126595166-GTG-CTC

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001182.5(ALDH7A1):​c.31_33delinsGAG​(p.His11Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: ALDH7A1 NM_001182.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 1.54

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 5-126595166-GTG-CTC is Benign according to our data. Variant chr5-126595166-GTG-CTC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204861.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH7A1	NM_001182.5	c.31_33delinsGAG	p.His11Glu	missense_variant	1/18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001202404.2	c.31_33delinsGAG	p.His11Glu	missense_variant	1/16		NP_001189333.2
ALDH7A1	NM_001201377.2	c.-54_-52delinsGAG		5_prime_UTR_variant	1/18		NP_001188306.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.31_33delinsGAG	p.His11Glu	missense_variant	1/18	1	NM_001182.5	ENSP00000387123	P4

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 05, 2015

c.31_33delCACinsGAG: p.His11Glu (H11E) in exon 1 of the ALDH7A1 gene (NM_001182.4). The normal sequence with the bases that are deleted in braces followed by the inserted bases in brackets is: CTGTGTGTG{CAC}[GAG] GCTG. The c.31_33delCACinsGAG variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The c.31_33delCACinsGAG variant results in an in-frame deletion of a single Histidine residue and the insertion of a single Glutamic acid residue, denoted p.His11Glu (H11E). The H11E variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis predicts this variant likely does not alter the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. The variant is found in INFANT-EPI panel(s). -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2018

The c.31_33delCACinsGAG variant, located in coding exon 1 of the ALDH7A1 gene, results from an in-frame deletion of CAC and insertion of GAG at nucleotide positions 31 to 33. This results in the substitution of the histidine residue for a glutamic acid residue at codon 11, an amino acid with highly similar properties. Based on data from gnomAD, this alteration was deposited as two separate missense substitutions (c.31C>G; c.33C>G) each with an overall frequency of approximately 0.01% (21/184172; 20/183384) total alleles studied. The highest observed frequency for each was approximately 0.07% (19/25066; 18/25014) of Latino alleles. This amino acid position is poorly conserved in available vertebrate species. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Pyridoxine-dependent epilepsy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs796052269; hg19: chr5-125930858;