6-24504968-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 4P and 20B. PM1 PM5 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080.3(ALDH5A1):c.709G>T(p.Ala237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,082 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A237T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 33)
  • Exomes 𝑓: 0.015 (210 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.50

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001080.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-24504968-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 904924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.012225747).
• BP6: Variant 6-24504968-G-T is Benign according to our data. Variant chr6-24504968-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 218854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24504968-G-T is described in Lovd as [Pathogenic]. Variant chr6-24504968-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1847/152302) while in subpopulation NFE AF= 0.0192 (1303/68032). AF 95% confidence interval is 0.0183. There are 21 homozygotes in gnomad4. There are 833 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.709G>T	p.Ala237Ser	missense_variant	4/10	ENST00000357578.8
ALDH5A1	NM_170740.1	c.709G>T	p.Ala237Ser	missense_variant	4/11
ALDH5A1	NM_001368954.1	c.709G>T	p.Ala237Ser	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.709G>T	p.Ala237Ser	missense_variant	4/10	1	NM_001080.3	P1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1847 AN: 152184 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.00957

GnomAD3 exomes AF: 0.0114 AC: 2856 AN: 251372 Hom.: 26 AF XY: 0.0115 AC XY: 1568 AN XY: 135880

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00714

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.00559

Gnomad FIN exome AF: 0.00781

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0145 AC: 21242 AN: 1461780 Hom.: 210 Cov.: 33 AF XY: 0.0144 AC XY: 10476 AN XY: 727198

Gnomad4 AFR exome AF: 0.00278

Gnomad4 AMR exome AF: 0.00745

Gnomad4 ASJ exome AF: 0.00719

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.00674

Gnomad4 FIN exome AF: 0.00901

Gnomad4 NFE exome AF: 0.0167

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0121 AC: 1847 AN: 152302 Hom.: 21 Cov.: 33 AF XY: 0.0112 AC XY: 833 AN XY: 74466

Gnomad4 AFR AF: 0.00274

Gnomad4 AMR AF: 0.0124

Gnomad4 ASJ AF: 0.00577

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.00801

Gnomad4 NFE AF: 0.0192

Gnomad4 OTH AF: 0.00947

Alfa AF: 0.0168 Hom.: 87

Bravo AF: 0.0120

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0171 AC: 66

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0199 AC: 171

ExAC AF: 0.0119 AC: 1449

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0200

EpiControl AF: 0.0187

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 21, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Oct 12, 2015	- -

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 06, 2018

This variant is associated with the following publications: (PMID: 29895405, 19164088, 12208142) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.070
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D;T;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;D
MetaRNN	Benign	0.012	T;T;T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	2.0	M;.;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D;D;D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D;D;D
Sift4G	Uncertain	0.051	T;T;T
Polyphen		0.68	P;.;.
Vest4		0.60
MPC		0.90
ClinPred		0.031	T
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.78
gMVP		0.80

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

Other links and lift over

dbSNP: rs62621664; hg19: chr6-24505196; COSMIC: COSV62373527;