5-126552104-T-C

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001182.5(ALDH7A1):c.1234A>G(p.Thr412Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00244 in 1,614,082 control chromosomes in the GnomAD database, including 112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0033 ( 15 hom., cov: 32)

Exomes 𝑓: 0.0023 ( 97 hom. )

Consequence

ALDH7A1
NM_001182.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 5.05

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0056553185).

BP6

Variant 5-126552104-T-C is Benign according to our data. Variant chr5-126552104-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 128345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126552104-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0711 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH7A1	NM_001182.5 link	c.1234A>G	p.Thr412Ala	missense_variant	Exon 14 of 18	ENST00000409134.8	NP_001173.2	P49419-1
ALDH7A1	NM_001201377.2 link	c.1150A>G	p.Thr384Ala	missense_variant	Exon 14 of 18		NP_001188306.1	P49419-2
ALDH7A1	NM_001202404.2 link	c.1042A>G	p.Thr348Ala	missense_variant	Exon 12 of 16		NP_001189333.2	P49419-4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH7A1	ENST00000409134.8 link	c.1234A>G	p.Thr412Ala	missense_variant	Exon 14 of 18	1	NM_001182.5	ENSP00000387123.3		P49419-1

Frequencies

GnomAD3 genomes

AF:

0.00333

AC:

507

AN:

152168

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000603

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.0118

Gnomad EAS

AF:

0.0771

Gnomad SAS

AF:

0.00497

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00683

AC:

1715

AN:

251254

Hom.:

AF XY:

0.00641

AC XY:

870

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.0115

Gnomad EAS exome

AF:

0.0813

Gnomad SAS exome

AF:

0.00131

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000273

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00235

AC:

3433

AN:

1461796

Hom.:

Cov.:

AF XY:

0.00232

AC XY:

1689

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.0118

Gnomad4 EAS exome

AF:

0.0645

Gnomad4 SAS exome

AF:

0.00134

Gnomad4 FIN exome

AF:

0.000187

Gnomad4 NFE exome

AF:

0.000138

Gnomad4 OTH exome

AF:

0.00447

GnomAD4 genome

AF:

0.00333

AC:

507

AN:

152286

Hom.:

Cov.:

AF XY:

0.00373

AC XY:

278

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000602

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.0118

Gnomad4 EAS

AF:

0.0773

Gnomad4 SAS

AF:

0.00498

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000896

Hom.:

Bravo

AF:

0.00371

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.00668

AC:

811

Asia WGS

AF:

0.0320

AC:

110

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyridoxine-dependent epilepsy

Benign:4

Apr 11, 2023

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not specified

Benign:3

Feb 24, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Jun 05, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 05, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

0.12

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

DANN

Benign

0.77

DEOGEN2

Benign

0.16

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

Eigen

Benign

-0.0024

Eigen_PC

Benign

0.058

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

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

MetaRNN

Benign

0.0057

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

MetaSVM

Benign

-0.65

MutationAssessor

Uncertain

2.5

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

PrimateAI

Benign

0.45

PROVEAN

Pathogenic

-4.9

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

REVEL

Uncertain

0.59

Sift

Benign

0.59

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

Sift4G

Benign

0.90

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

Polyphen

0.28

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

Vest4

0.48, 0.51

MVP

0.87

MPC

0.27

ClinPred

0.10

GERP RS

4.9

Varity_R

0.71

gMVP

0.86

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