rs12514417

Positions:

chr5-126552023-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000409134.8(ALDH7A1):c.1315A>C(p.Lys439Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0959 in 1,609,982 control chromosomes in the GnomAD database, including 8,257 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.088 ( 711 hom., cov: 32)

Exomes 𝑓: 0.097 ( 7546 hom. )

Consequence

ALDH7A1
ENST00000409134.8 missense, splice_region

Scores

Splicing: ADA: 0.0002109

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 4.92

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 Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 uncertain in ENST00000409134.8

BP4

Computational evidence support a benign effect (MetaRNN=0.00204584).

BP6

Variant 5-126552023-T-G is Benign according to our data. Variant chr5-126552023-T-G is described in ClinVar as [Benign]. Clinvar id is 128346.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126552023-T-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
ALDH7A1	NM_001182.5 linkuse as main transcript	c.1315A>C	p.Lys439Gln	missense_variant, splice_region_variant	14/18	ENST00000409134.8	NP_001173.2
ALDH7A1	NM_001201377.2 linkuse as main transcript	c.1231A>C	p.Lys411Gln	missense_variant, splice_region_variant	14/18		NP_001188306.1
ALDH7A1	NM_001202404.2 linkuse as main transcript	c.1123A>C	p.Lys375Gln	missense_variant, splice_region_variant	12/16		NP_001189333.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8 linkuse as main transcript	c.1315A>C	p.Lys439Gln	missense_variant, splice_region_variant	14/18	1	NM_001182.5	ENSP00000387123	P4	P49419-1

Frequencies

GnomAD3 genomes

AF:

0.0874

AC:

13300

AN:

152114

Hom.:

705

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0436

Gnomad AMI

AF:

0.0989

Gnomad AMR

AF:

0.141

Gnomad ASJ

AF:

0.0812

Gnomad EAS

AF:

0.151

Gnomad SAS

AF:

0.0783

Gnomad FIN

AF:

0.128

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0925

Gnomad OTH

AF:

0.0765

GnomAD3 exomes

AF:

0.114

AC:

28669

AN:

251026

Hom.:

2132

AF XY:

0.109

AC XY:

14722

AN XY:

135658

show subpopulations

Gnomad AFR exome

AF:

0.0455

Gnomad AMR exome

AF:

0.241

Gnomad ASJ exome

AF:

0.0768

Gnomad EAS exome

AF:

0.142

Gnomad SAS exome

AF:

0.0789

Gnomad FIN exome

AF:

0.133

Gnomad NFE exome

AF:

0.0908

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.0968

AC:

141066

AN:

1457750

Hom.:

7546

Cov.:

AF XY:

0.0956

AC XY:

69359

AN XY:

725456

show subpopulations

Gnomad4 AFR exome

AF:

0.0402

Gnomad4 AMR exome

AF:

0.226

Gnomad4 ASJ exome

AF:

0.0752

Gnomad4 EAS exome

AF:

0.123

Gnomad4 SAS exome

AF:

0.0793

Gnomad4 FIN exome

AF:

0.130

Gnomad4 NFE exome

AF:

0.0930

Gnomad4 OTH exome

AF:

0.0923

GnomAD4 genome

AF:

0.0875

AC:

13322

AN:

152232

Hom.:

711

Cov.:

AF XY:

0.0893

AC XY:

6645

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.0436

Gnomad4 AMR

AF:

0.141

Gnomad4 ASJ

AF:

0.0812

Gnomad4 EAS

AF:

0.151

Gnomad4 SAS

AF:

0.0779

Gnomad4 FIN

AF:

0.128

Gnomad4 NFE

AF:

0.0925

Gnomad4 OTH

AF:

0.0799

Alfa

AF:

0.0912

Hom.:

1889

Bravo

AF:

0.0906

TwinsUK

AF:

0.0965

AC:

358

ALSPAC

AF:

0.0893

AC:

344

ESP6500AA

AF:

0.0445

AC:

196

ESP6500EA

AF:

0.0887

AC:

763

ExAC

AF:

0.106

AC:

12860

Asia WGS

AF:

0.133

AC:

461

AN:

3478

EpiCase

AF:

0.0862

EpiControl

AF:

0.0855

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 20% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 19. Only high quality variants are reported. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Pyridoxine-dependent epilepsy

Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Nov 14, 2016	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 24, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.032

T;T;T;.;T;.;.;.

Eigen

Benign

-0.20

Eigen_PC

Benign

-0.076

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.68

T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0020

T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.81

MutationAssessor

Uncertain

2.1

.;M;.;.;.;.;.;.

MutationTaster

Benign

0.90

P;P;P

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.2

.;N;.;.;.;.;.;N

REVEL

Uncertain

0.32

Sift

Benign

0.21

.;T;.;.;.;.;.;T

Sift4G

Benign

0.27

.;T;.;.;.;.;.;T

Polyphen

0.0010

.;B;.;.;.;.;.;.

Vest4

0.23, 0.20

MPC

0.17

ClinPred

0.025

GERP RS

3.5

Varity_R

0.46

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00021

dbscSNV1_RF

Benign

0.0020

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