rs79544459

chr5-126577223-A-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001182.5(ALDH7A1):c.518-12T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0211 in 1,614,016 control chromosomes in the GnomAD database, including 507 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (118 hom., cov: 31)
  • Exomes 𝑓: 0.020 (389 hom.)
• Consequence: ALDH7A1 NM_001182.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001611
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.192

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 5-126577223-A-C is Benign according to our data. Variant chr5-126577223-A-C is described in ClinVar as [Benign]. Clinvar id is 257610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126577223-A-C is described in Lovd as [Benign]. Variant chr5-126577223-A-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0686 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH7A1	NM_001182.5	c.518-12T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000409134.8
ALDH7A1	NM_001201377.2	c.434-12T>G		splice_polypyrimidine_tract_variant, intron_variant
ALDH7A1	NM_001202404.2	c.518-12T>G		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.518-12T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001182.5	P4

Frequencies

GnomAD3 genomes AF: 0.0329 AC: 5004 AN: 152154 Hom.: 118 Cov.: 31

Gnomad AFR AF: 0.0707

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0232

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0205

Gnomad OTH AF: 0.0301

GnomAD3 exomes AF: 0.0196 AC: 4918 AN: 251144 Hom.: 76 AF XY: 0.0183 AC XY: 2488 AN XY: 135738

Gnomad AFR exome AF: 0.0715

Gnomad AMR exome AF: 0.0188

Gnomad ASJ exome AF: 0.0520

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00278

Gnomad FIN exome AF: 0.00670

Gnomad NFE exome AF: 0.0192

Gnomad OTH exome AF: 0.0285

GnomAD4 exome AF: 0.0199 AC: 29035 AN: 1461744 Hom.: 389 Cov.: 31 AF XY: 0.0194 AC XY: 14074 AN XY: 727150

Gnomad4 AFR exome AF: 0.0765

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.0489

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00306

Gnomad4 FIN exome AF: 0.00687

Gnomad4 NFE exome AF: 0.0198

Gnomad4 OTH exome AF: 0.0236

GnomAD4 genome AF: 0.0329 AC: 5014 AN: 152272 Hom.: 118 Cov.: 31 AF XY: 0.0317 AC XY: 2360 AN XY: 74464

Gnomad4 AFR AF: 0.0708

Gnomad4 AMR AF: 0.0231

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00290

Gnomad4 FIN AF: 0.00659

Gnomad4 NFE AF: 0.0205

Gnomad4 OTH AF: 0.0298

Alfa AF: 0.0299 Hom.: 17

Bravo AF: 0.0364

Asia WGS AF: 0.00693 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pyridoxine-dependent epilepsy Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	5.3
Dann	Benign	0.43

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.11
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

LitVar

Other links and lift over

dbSNP: rs79544459; hg19: chr5-125912915;