5-126541943-A-G

Position:

• chr5-126541943-A-G

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.*3022T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 145,596 control chromosomes in the GnomAD database, including 20,944 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.53 (20944 hom., cov: 29)
  • Failed GnomAD Quality Control
• Consequence: ALDH7A1 NM_001182.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.84

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=-0.81).
• BP6: Variant 5-126541943-A-G is Benign according to our data. Variant chr5-126541943-A-G is described in ClinVar as [Benign]. Clinvar id is 350520.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.612 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH7A1	NM_001182.5	c.*3022T>C		3_prime_UTR_variant	18/18	ENST00000409134.8
ALDH7A1	NM_001201377.2	c.*3022T>C		3_prime_UTR_variant	18/18
ALDH7A1	NM_001202404.2	c.*3022T>C		3_prime_UTR_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH7A1	ENST00000409134.8	c.*3022T>C		3_prime_UTR_variant	18/18	1	NM_001182.5	P4
ALDH7A1	ENST00000635851.1	c.1564-955T>C		intron_variant		5
ALDH7A1	ENST00000637782.1	c.1565+4381T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.532 AC: 77431 AN: 145478 Hom.: 20935 Cov.: 29

Gnomad AFR AF: 0.377

Gnomad AMI AF: 0.499

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.517

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.631

Gnomad FIN AF: 0.637

Gnomad MID AF: 0.542

Gnomad NFE AF: 0.613

Gnomad OTH AF: 0.546

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.532 AC: 77463 AN: 145596 Hom.: 20944 Cov.: 29 AF XY: 0.534 AC XY: 37807 AN XY: 70788

Gnomad4 AFR AF: 0.377

Gnomad4 AMR AF: 0.493

Gnomad4 ASJ AF: 0.517

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.631

Gnomad4 FIN AF: 0.637

Gnomad4 NFE AF: 0.613

Gnomad4 OTH AF: 0.543

Alfa AF: 0.443 Hom.: 1882

Bravo AF: 0.488

Asia WGS AF: 0.501 AC: 1737 AN: 3466

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	-0.81
CADD	Benign	4.3
DANN	Benign	0.62

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: rs2035471; hg19: chr5-125877635;