rs776978579

Variant names:

• chr6-24533582-A-G
• rs776978579
• NM_001080.3:c.1478A>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_001080.3(ALDH5A1):​c.1478A>G​(p.Asn493Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000821 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N493K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 8.66
• Publications: 1 publications found

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]

ALDH5A1 Gene-Disease associations (from GenCC):

• succinic semialdehyde dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 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, 9 uncertain in NM_001080.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 0.73405 (below the threshold of 3.09). Trascript score misZ: 0.28023 (below the threshold of 3.09). GenCC associations: The gene is linked to succinic semialdehyde dehydrogenase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 6-24533582-A-G is Pathogenic according to our data. Variant chr6-24533582-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 529487.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.1478A>G	p.Asn493Ser	missense	Exon 10 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.1517A>G	p.Asn506Ser	missense	Exon 11 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.1334A>G	p.Asn445Ser	missense	Exon 9 of 9	NP_001355883.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.1478A>G	p.Asn493Ser	missense	Exon 10 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.1517A>G	p.Asn506Ser	missense	Exon 11 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.1460A>G	p.Asn487Ser	missense	Exon 11 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251492 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000821 AC: 12 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727248

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000108 AC: 12 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	1	-	Succinate-semialdehyde dehydrogenase deficiency (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		8.7
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.87
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.94		Gain of phosphorylation at N493 (P = 0.1062)
MVP		0.98
MPC		0.84
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.96
gMVP		0.97
Mutation Taster		=13/87	disease causing

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

Other links and lift over

dbSNP: rs776978579; hg19: chr6-24533810; COSMIC: COSV62373595;