chr6-24495028-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001080.3(ALDH5A1):​c.32G>A​(p.Gly11Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000163 in 1,345,668 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000092 ( 0 hom. )

Consequence

ALDH5A1
NM_001080.3 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:1

Conservation

PhyloP100: 1.07
Variant links:
Genes affected
ALDH5A1 (HGNC:408): (aldehyde dehydrogenase 5 family member A1) This protein belongs to the aldehyde dehydrogenase family of proteins. This gene encodes a mitochondrial NAD(+)-dependent succinic semialdehyde dehydrogenase. A deficiency of this enzyme, known as 4-hydroxybutyricaciduria, is a rare inborn error in the metabolism of the neurotransmitter 4-aminobutyric acid (GABA). In response to the defect, physiologic fluids from patients accumulate GHB, a compound with numerous neuromodulatory properties. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]
GPLD1 (HGNC:4459): (glycosylphosphatidylinositol specific phospholipase D1) Many proteins are tethered to the extracellular face of eukaryotic plasma membranes by a glycosylphosphatidylinositol (GPI) anchor. The GPI-anchor is a glycolipid found on many blood cells. The protein encoded by this gene is a GPI degrading enzyme. Glycosylphosphatidylinositol specific phospholipase D1 hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans, thereby releasing the attached protein from the plasma membrane. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.08963248).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ALDH5A1NM_001080.3 linkuse as main transcriptc.32G>A p.Gly11Glu missense_variant 1/10 ENST00000357578.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALDH5A1ENST00000357578.8 linkuse as main transcriptc.32G>A p.Gly11Glu missense_variant 1/101 NM_001080.3 P1P51649-1

Frequencies

GnomAD3 genomes
AF:
0.0000724
AC:
11
AN:
152028
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
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:
0.000478
GnomAD4 exome
AF:
0.00000922
AC:
11
AN:
1193640
Hom.:
0
Cov.:
31
AF XY:
0.00000690
AC XY:
4
AN XY:
580112
show subpopulations
Gnomad4 AFR exome
AF:
0.000316
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000329
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000102
Gnomad4 OTH exome
AF:
0.0000209
GnomAD4 genome
AF:
0.0000724
AC:
11
AN:
152028
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74256
show subpopulations
Gnomad4 AFR
AF:
0.000193
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000793
ESP6500AA
AF:
0.000359
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000180
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 30, 2018- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 15, 2019In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Succinate-semialdehyde dehydrogenase deficiency Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsJul 12, 2021- -
Likely benign, criteria provided, single submitterclinical testingInvitaeDec 14, 2023- -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsNov 22, 2023The c.32G>A (p.G11E) alteration is located in exon 1 (coding exon 1) of the ALDH5A1 gene. This alteration results from a G to A substitution at nucleotide position 32, causing the glycine (G) at amino acid position 11 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.074
T
BayesDel_noAF
Benign
-0.34
CADD
Benign
9.3
DANN
Benign
0.95
DEOGEN2
Benign
0.090
T;T;.
Eigen
Benign
-1.0
Eigen_PC
Benign
-1.0
FATHMM_MKL
Benign
0.039
N
LIST_S2
Benign
0.68
T;T;T
M_CAP
Uncertain
0.27
D
MetaRNN
Benign
0.090
T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.34
N;.;N
MutationTaster
Benign
1.0
N;N;N;N
PrimateAI
Uncertain
0.65
T
PROVEAN
Benign
0.060
N;N;N
REVEL
Benign
0.11
Sift
Benign
0.19
T;T;T
Sift4G
Benign
0.32
T;T;T
Polyphen
0.0010
B;.;.
Vest4
0.22
MVP
0.67
MPC
0.38
ClinPred
0.023
T
GERP RS
1.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.038
gMVP
0.47

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.

Other links and lift over

dbSNP: rs373315916; hg19: chr6-24495256; COSMIC: COSV62372982; API