5-126542466-C-T

Position:

• chr5-126542466-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001182.5(ALDH7A1):​c.*2499G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.529 in 151,894 control chromosomes in the GnomAD database, including 22,040 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.53 (22022 hom., cov: 30)
  • Exomes 𝑓: 0.61 (18 hom.)
• Consequence: ALDH7A1 NM_001182.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.446

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 5-126542466-C-T is Benign according to our data. Variant chr5-126542466-C-T is described in ClinVar as [Benign]. Clinvar id is 350531.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.602 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH7A1	NM_001182.5	c.*2499G>A		3_prime_UTR_variant	18/18	ENST00000409134.8
ALDH7A1	NM_001201377.2	c.*2499G>A		3_prime_UTR_variant	18/18
ALDH7A1	NM_001202404.2	c.*2499G>A		3_prime_UTR_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.*2499G>A		3_prime_UTR_variant	18/18	1	NM_001182.5	P4
ALDH7A1	ENST00000635851.1	c.1564-1478G>A		intron_variant		5
ALDH7A1	ENST00000637782.1	c.1565+3858G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.529 AC: 80265 AN: 151686 Hom.: 22005 Cov.: 30

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.468

Gnomad ASJ AF: 0.514

Gnomad EAS AF: 0.437

Gnomad SAS AF: 0.610

Gnomad FIN AF: 0.621

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.530

GnomAD4 exome AF: 0.611 AC: 55 AN: 90 Hom.: 18 Cov.: 0 AF XY: 0.614 AC XY: 43 AN XY: 70

Gnomad4 AFR exome AF: 0.500

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 0.500

Gnomad4 NFE exome AF: 0.615

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.529 AC: 80309 AN: 151804 Hom.: 22022 Cov.: 30 AF XY: 0.529 AC XY: 39234 AN XY: 74164

Gnomad4 AFR AF: 0.404

Gnomad4 AMR AF: 0.468

Gnomad4 ASJ AF: 0.514

Gnomad4 EAS AF: 0.437

Gnomad4 SAS AF: 0.611

Gnomad4 FIN AF: 0.621

Gnomad4 NFE AF: 0.607

Gnomad4 OTH AF: 0.528

Alfa AF: 0.539 Hom.: 3484

Bravo AF: 0.505

Asia WGS AF: 0.505 AC: 1757 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pyridoxine-dependent epilepsy Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.3
DANN	Benign	0.35

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

LitVar

Other links and lift over

dbSNP: rs7715516; hg19: chr5-125878158;