Genetic Variant ALDH7A1:c.246+6A>G (chr5-126593345-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001182.5(ALDH7A1):c.246+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000711 in 1,407,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ALDH7A1
NM_001182.5 splice_region, intron

Scores

Splicing: ADA: 0.000006213

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0930

Publications

0 publications found

Variant links:

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: Illumina, Orphanet, ClinGen
pyridoxine-dependent epilepsy caused by ALDH7A1 mutant
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics

ALDH7A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein
ALDH7A1	NM_001182.5 link	c.246+6A>G	splice_region_variant, intron_variant	Intron 2 of 17	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2 link	c.162+6A>G	splice_region_variant, intron_variant	Intron 2 of 17		NP_001188306.1
ALDH7A1	NM_001202404.2 link	c.246+6A>G	splice_region_variant, intron_variant	Intron 2 of 15		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8 link	c.246+6A>G		splice_region_variant, intron_variant	Intron 2 of 17	1	NM_001182.5	ENSP00000387123.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000454

AC:

AN:

220354

AF XY:

0.00000839

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.11e-7

AC:

AN:

1407326

Hom.:

Cov.:

AF XY:

0.00000143

AC XY:

AN XY:

700402

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29858

American (AMR)

AF:

0.00

AC:

AN:

42664

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25030

East Asian (EAS)

AF:

0.00

AC:

AN:

38458

South Asian (SAS)

AF:

0.0000121

AC:

AN:

82538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4824

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1075414

Other (OTH)

AF:

0.00

AC:

AN:

58000

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

2.0

(source)

DANN

Benign

0.75

PhyloP100

-0.093

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0000062

dbscSNV1_RF

Benign

0.0

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over