5-126542466-C-T

Variant names:

• chr5-126542466-C-T
• rs7715516
• NM_001182.5:c.*2499G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• pyridoxine-dependent epilepsy

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen, Illumina
• pyridoxine-dependent epilepsy caused by ALDH7A1 mutant

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001182.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH7A1	NM_001182.5	MANE Select	c.*2499G>A		3_prime_UTR	Exon 18 of 18	NP_001173.2	P49419-1
	ALDH7A1	NM_001201377.2		c.*2499G>A		3_prime_UTR	Exon 18 of 18	NP_001188306.1	P49419-2
	ALDH7A1	NM_001202404.2		c.*2499G>A		3_prime_UTR	Exon 16 of 16	NP_001189333.2	P49419-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH7A1	ENST00000409134.8	TSL:1 MANE Select	c.*2499G>A		3_prime_UTR	Exon 18 of 18	ENSP00000387123.3	P49419-1
	ALDH7A1	ENST00000635851.1	TSL:5	c.1563-1478G>A		intron	N/A	ENSP00000490819.1	A0A1B0GW82
	ALDH7A1	ENST00000637782.1	TSL:5	c.1565+3858G>A		intron	N/A	ENSP00000490024.1	A0A1B0GUA1

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

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 2 AN: 2

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.615 AC: 48 AN: 78

Other (OTH) AF: 0.500 AC: 2 AN: 4

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

African (AFR) AF: 0.404 AC: 16685 AN: 41348

American (AMR) AF: 0.468 AC: 7139 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.514 AC: 1782 AN: 3470

East Asian (EAS) AF: 0.437 AC: 2250 AN: 5146

South Asian (SAS) AF: 0.611 AC: 2935 AN: 4806

European-Finnish (FIN) AF: 0.621 AC: 6543 AN: 10544

Middle Eastern (MID) AF: 0.534 AC: 157 AN: 294

European-Non Finnish (NFE) AF: 0.607 AC: 41262 AN: 67936

Other (OTH) AF: 0.528 AC: 1108 AN: 2098

Alfa AF: 0.535 Hom.: 3560

Bravo AF: 0.505

Asia WGS AF: 0.505 AC: 1757 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Pyridoxine-dependent epilepsy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.3
DANN	Benign	0.35
PhyloP100		-0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7715516; hg19: chr5-125878158;