rs58528748

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 1P and 4B. PP2BP4_Strong

The ENST00000409134.8(ALDH7A1):c.203C>A(p.Thr68Asn) variant causes a missense change. The variant allele was found at a frequency of 0.0000607 in 1,613,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

ALDH7A1
ENST00000409134.8 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 5.37

Publications

2 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 -3 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 0.36846 (below the threshold of 3.09). Trascript score misZ: 0.93117 (below the threshold of 3.09). GenCC associations: The gene is linked to pyridoxine-dependent epilepsy, pyridoxine-dependent epilepsy caused by ALDH7A1 mutant.

BP4

Computational evidence support a benign effect (MetaRNN=0.055043638).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000409134.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALDH7A1	NM_001182.5	MANE Select	c.203C>A	p.Thr68Asn	missense	Exon 2 of 18	NP_001173.2
ALDH7A1	NM_001201377.2		c.119C>A	p.Thr40Asn	missense	Exon 2 of 18	NP_001188306.1
ALDH7A1	NM_001202404.2		c.203C>A	p.Thr68Asn	missense	Exon 2 of 16	NP_001189333.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALDH7A1	ENST00000409134.8	TSL:1 MANE Select	c.203C>A	p.Thr68Asn	missense	Exon 2 of 18	ENSP00000387123.3
ALDH7A1	ENST00000636879.1	TSL:5	c.203C>A	p.Thr68Asn	missense	Exon 2 of 19	ENSP00000490811.1
ALDH7A1	ENST00000635851.1	TSL:5	c.200C>A	p.Thr67Asn	missense	Exon 2 of 18	ENSP00000490819.1

Frequencies

GnomAD3 genomes

AF:

0.000310

AC:

AN:

151606

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00109

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000659

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.0000995

AC:

AN:

251374

AF XY:

0.000103

show subpopulations

Gnomad AFR exome

AF:

0.00123

Gnomad AMR exome

AF:

0.000145

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:

0.0000349

AC:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727148

show subpopulations

African (AFR)

AF:

0.00114

AC:

AN:

33474

American (AMR)

AF:

0.000224

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111994

Other (OTH)

AF:

0.0000497

AC:

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000310

AC:

AN:

151722

Hom.:

Cov.:

AF XY:

0.000310

AC XY:

AN XY:

74102

show subpopulations

African (AFR)

AF:

0.00109

AC:

AN:

41302

American (AMR)

AF:

0.0000658

AC:

AN:

15204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67976

Other (OTH)

AF:

0.000476

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.000412

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000148

AC:

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pyridoxine-dependent epilepsy (4)

Inborn genetic diseases (1)

Intractable seizure (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.020

Eigen

Uncertain

0.23

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

M_CAP

Uncertain

0.089

MetaRNN

Benign

0.055

MetaSVM

Uncertain

0.27

MutationAssessor

Benign

1.2

PhyloP100

5.4

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.84

REVEL

Uncertain

0.41

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.051

Polyphen

0.61

Vest4

0.55

MVP

0.95

MPC

0.44

ClinPred

0.066

GERP RS

3.8

Varity_R

0.67

gMVP

0.79

Mutation Taster

=37/63

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over