5-126545018-T-C

Position:

chr5-126545018-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_001182.5(ALDH7A1):c.1567A>G(p.Thr523Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00544 in 1,604,892 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0039 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0056 ( 25 hom. )

Consequence

ALDH7A1
NM_001182.5 missense, splice_region

Scores

Splicing: ADA: 0.7900

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 6.90

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 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001182.5

BP4

Computational evidence support a benign effect (MetaRNN=0.015203327).

BP6

Variant 5-126545018-T-C is Benign according to our data. Variant chr5-126545018-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 194825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-126545018-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00395 (601/152336) while in subpopulation NFE AF= 0.0055 (374/68034). AF 95% confidence interval is 0.00504. There are 3 homozygotes in gnomad4. There are 294 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
ALDH7A1	NM_001182.5 linkuse as main transcript	c.1567A>G	p.Thr523Ala	missense_variant, splice_region_variant	18/18	ENST00000409134.8
ALDH7A1	NM_001201377.2 linkuse as main transcript	c.1483A>G	p.Thr495Ala	missense_variant, splice_region_variant	18/18
ALDH7A1	NM_001202404.2 linkuse as main transcript	c.1375A>G	p.Thr459Ala	missense_variant, splice_region_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH7A1	ENST00000409134.8 linkuse as main transcript	c.1567A>G	p.Thr523Ala	missense_variant, splice_region_variant	18/18	1	NM_001182.5	P4	P49419-1

Frequencies

GnomAD3 genomes

AF:

0.00395

AC:

601

AN:

152218

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000941

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00164

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.0103

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00550

Gnomad OTH

AF:

0.00334

GnomAD3 exomes

AF:

0.00448

AC:

1124

AN:

251000

Hom.:

AF XY:

0.00454

AC XY:

616

AN XY:

135724

show subpopulations

Gnomad AFR exome

AF:

0.00129

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.0117

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00320

Gnomad FIN exome

AF:

0.00981

Gnomad NFE exome

AF:

0.00529

Gnomad OTH exome

AF:

0.00556

GnomAD4 exome

AF:

0.00560

AC:

8132

AN:

1452556

Hom.:

Cov.:

AF XY:

0.00536

AC XY:

3875

AN XY:

723232

show subpopulations

Gnomad4 AFR exome

AF:

0.00120

Gnomad4 AMR exome

AF:

0.00134

Gnomad4 ASJ exome

AF:

0.0112

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00378

Gnomad4 FIN exome

AF:

0.0102

Gnomad4 NFE exome

AF:

0.00597

Gnomad4 OTH exome

AF:

0.00456

GnomAD4 genome

AF:

0.00395

AC:

601

AN:

152336

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

294

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000938

Gnomad4 AMR

AF:

0.00163

Gnomad4 ASJ

AF:

0.0101

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00249

Gnomad4 FIN

AF:

0.0103

Gnomad4 NFE

AF:

0.00550

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00502

Hom.:

Bravo

AF:

0.00330

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00804

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00814

AC:

ExAC

AF:

0.00448

AC:

544

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.00409

EpiControl

AF:

0.00427

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pyridoxine-dependent epilepsy

Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Mar 31, 2015	- -

not specified

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 18, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 19, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2016	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. -

not provided

Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 09, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ALDH7A1: PP3, BS1, BS2 -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 13, 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

Uncertain

0.51

BayesDel_addAF

Uncertain

0.071

BayesDel_noAF

Pathogenic

0.33

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

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

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

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

MetaRNN

Benign

0.015

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

MetaSVM

Uncertain

0.60

MutationAssessor

Benign

1.0

L;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-4.7

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

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.016

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

Polyphen

1.0

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

Vest4

0.78

MVP

0.83

MPC

0.65

ClinPred

0.019

GERP RS

4.8

Varity_R

0.90

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.79

dbscSNV1_RF

Benign

0.48

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