rs185042766

chr6-24495126-C-Gchr6-24495126-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS1

The NM_001080.3(ALDH5A1):c.130C>G(p.Leu44Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000477 in 1,382,708 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (2 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.340

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0041862726).
• BP6: Variant 6-24495126-C-G is Benign according to our data. Variant chr6-24495126-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 356126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00247 (375/151868) while in subpopulation AFR AF= 0.00855 (355/41522). AF 95% confidence interval is 0.00782. There are 1 homozygotes in gnomad4. There are 192 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.130C>G	p.Leu44Val	missense_variant	1/10	ENST00000357578.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.130C>G	p.Leu44Val	missense_variant	1/10	1	NM_001080.3	P1

Frequencies

GnomAD3 genomes AF: 0.00240 AC: 364 AN: 151760 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00831

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000919

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: 0.0000442

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.000470 AC: 12 AN: 25538 Hom.: 0 AF XY: 0.000392 AC XY: 6 AN XY: 15302

Gnomad AFR exome AF: 0.0161

Gnomad AMR exome AF: 0.000216

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000395

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000199

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000231 AC: 284 AN: 1230840 Hom.: 2 Cov.: 31 AF XY: 0.000206 AC XY: 124 AN XY: 601754

Gnomad4 AFR exome AF: 0.00899

Gnomad4 AMR exome AF: 0.000495

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000914

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000159

Gnomad4 OTH exome AF: 0.000673

GnomAD4 genome AF: 0.00247 AC: 375 AN: 151868 Hom.: 1 Cov.: 33 AF XY: 0.00259 AC XY: 192 AN XY: 74224

Gnomad4 AFR AF: 0.00855

Gnomad4 AMR AF: 0.000917

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000209 Hom.: 0

Bravo AF: 0.00279

ExAC AF: 0.000401 AC: 5

Asia WGS AF: 0.00204 AC: 7 AN: 3442

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 04, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 23, 2017	- -

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

ALDH5A1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 26, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	12
Dann	Benign	0.92
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.055	N
LIST_S2	Benign	0.61	T;T;T
MetaRNN	Benign	0.0042	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.;N
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.053
Sift	Benign	0.18	T;T;T
Sift4G	Benign	0.13	T;T;T
Polyphen		0.0070	B;.;.
Vest4		0.12
MVP		0.56
MPC		0.29
ClinPred		0.012	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.046
gMVP		0.16

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: rs185042766; hg19: chr6-24495354;