rs121912711

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The ENST00000409134.8(ALDH7A1):c.902A>T(p.Asn301Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,613,270 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N301S) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

ALDH7A1
ENST00000409134.8 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6

Conservation

PhyloP100: 5.93

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in ENST00000409134.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-126561094-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 954258.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.976

PP5

Variant 5-126561094-T-A is Pathogenic according to our data. Variant chr5-126561094-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18001.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126561094-T-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALDH7A1	NM_001182.5 linkuse as main transcript	c.902A>T	p.Asn301Ile	missense_variant	10/18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2 linkuse as main transcript	c.818A>T	p.Asn273Ile	missense_variant	10/18		NP_001188306.1
ALDH7A1	NM_001202404.2 linkuse as main transcript	c.902A>T	p.Asn301Ile	missense_variant	10/16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8 linkuse as main transcript	c.902A>T	p.Asn301Ile	missense_variant	10/18	1	NM_001182.5	ENSP00000387123	P4	P49419-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251328

Hom.:

AF XY:

0.0000294

AC XY:

AN XY:

135834

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000219

AC:

AN:

1460948

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

726704

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000279

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyridoxine-dependent epilepsy

Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 04, 2023	This sequence change replaces asparagine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 301 of the ALDH7A1 protein (p.Asn301Ile). This variant is present in population databases (rs121912711, gnomAD 0.004%). This missense change has been observed in individual(s) with pyridoxine-dependent epilepsy (PMID: 17068770, 20554659, 24664145). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is also known as p.Asn273Ile. ClinVar contains an entry for this variant (Variation ID: 18001). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ALDH7A1 protein function. Experimental studies have shown that this missense change affects ALDH7A1 function (PMID: 22784480). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	North West Genomic Laboratory Hub, Manchester University NHS Foundation Trust	Aug 26, 2021	Criteria Codes: PS3_Supp PM2 PM3_Str PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 28, 2023	- -

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2022

Published functional studies did not demonstrate detectable enzymatic activity (Coulter-Mackie et al., 2012); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 25553455, 27342130, 30005813, 24664145, 17068770, 26555630, 23022070, 31737911, 30043187, 32956737, 22784480) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.50

T;D;T;.;T;.;.;.;T

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.49

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.8

.;H;.;.;.;.;.;H;.

MutationTaster

Benign

1.0

A;A;A

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-8.8

.;D;.;.;.;.;.;D;.

REVEL

Pathogenic

0.85

Sift

Pathogenic

0.0

.;D;.;.;.;.;.;D;.

Sift4G

Pathogenic

0.0

.;D;.;.;.;.;.;D;.

Polyphen

1.0

.;D;.;.;.;.;.;.;.

Vest4

0.90, 0.93

MutPred

0.89

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);.;

MVP

0.98

MPC

0.73

ClinPred

1.0

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.99

gMVP

0.92

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over