rs115784602

Variant names:

• chr6-24520491-G-A
• rs115784602
• NM_001080.3:c.961G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001080.3(ALDH5A1):​c.961G>A​(p.Val321Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00467 in 1,614,160 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0034 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (20 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 3.03
• Publications: 14 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: Benign. The variant received -12 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01294896).
• BP6: Variant 6-24520491-G-A is Benign according to our data. Variant chr6-24520491-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 284072.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00339 (516/152284) while in subpopulation NFE AF = 0.00575 (391/68028). AF 95% confidence interval is 0.00528. There are 3 homozygotes in GnomAd4. There are 249 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.961G>A	p.Val321Met	missense	Exon 6 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.1000G>A	p.Val334Met	missense	Exon 7 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.817G>A	p.Val273Met	missense	Exon 5 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.961G>A	p.Val321Met	missense	Exon 6 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.1000G>A	p.Val334Met	missense	Exon 7 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.943G>A	p.Val315Met	missense	Exon 7 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes AF: 0.00338 AC: 514 AN: 152166 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00572

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00331 AC: 833 AN: 251464 AF XY: 0.00312

Gnomad AFR exome AF: 0.00117

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00863

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00407

Gnomad NFE exome AF: 0.00482

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00480 AC: 7017 AN: 1461876 Hom.: 20 Cov.: 33 AF XY: 0.00468 AC XY: 3406 AN XY: 727232

African (AFR) AF: 0.000836 AC: 28 AN: 33478

American (AMR) AF: 0.00141 AC: 63 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00746 AC: 195 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000812 AC: 70 AN: 86258

European-Finnish (FIN) AF: 0.00387 AC: 207 AN: 53420

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5766

European-Non Finnish (NFE) AF: 0.00562 AC: 6248 AN: 1112000

Other (OTH) AF: 0.00320 AC: 193 AN: 60394

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152284 Hom.: 3 Cov.: 32 AF XY: 0.00334 AC XY: 249 AN XY: 74460

African (AFR) AF: 0.000626 AC: 26 AN: 41560

American (AMR) AF: 0.00163 AC: 25 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00311 AC: 33 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00575 AC: 391 AN: 68028

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00476 Hom.: 7

Bravo AF: 0.00299

TwinsUK AF: 0.00378 AC: 14

ALSPAC AF: 0.00882 AC: 34

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00523 AC: 45

ExAC AF: 0.00312 AC: 379

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00491

EpiControl AF: 0.00528

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	4	not specified (4)
-	-	3	Succinate-semialdehyde dehydrogenase deficiency (3)
-	-	1	ALDH5A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.013	T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.83	L
PhyloP100		3.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.74	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.021	D
Polyphen		0.99	D
Vest4		0.27
MVP		0.80
MPC		0.36
ClinPred		0.010	T
GERP RS		5.5
Varity_R		0.57
gMVP		0.62
Mutation Taster		=86/14	polymorphism

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: rs115784602; hg19: chr6-24520719; COSMIC: COSV100708715; COSMIC: COSV100708715;