NM_001080.3:c.545C>A

Variant names:

• chr6-24503369-C-A
• rs3765310
• NM_001080.3:c.545C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP2

The NM_001080.3(ALDH5A1):​c.545C>A​(p.Pro182Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P182L) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.92
• Publications: 23 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: G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 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.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.545C>A	p.Pro182Gln	missense	Exon 3 of 10	NP_001071.1
	ALDH5A1	NM_170740.1		c.545C>A	p.Pro182Gln	missense	Exon 3 of 11	NP_733936.1
	ALDH5A1	NM_001368954.1		c.545C>A	p.Pro182Gln	missense	Exon 3 of 9	NP_001355883.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.545C>A	p.Pro182Gln	missense	Exon 3 of 10	ENSP00000350191.3
	ALDH5A1	ENST00000348925.2	TSL:1	c.545C>A	p.Pro182Gln	missense	Exon 3 of 11	ENSP00000314649.3
	ALDH5A1	ENST00000491546.5	TSL:5	c.461C>A	p.Pro154Gln	missense	Exon 2 of 9	ENSP00000417687.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.012	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Uncertain	0.28	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.9
PrimateAI	Benign	0.26	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.33
Sift	Benign	0.051	T
Sift4G	Uncertain	0.054	T
Polyphen		0.99	D
Vest4		0.26
MutPred		0.30		Gain of MoRF binding (P = 0.0611)
MVP		0.97
MPC		0.79
ClinPred		0.96	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.36
gMVP		0.61
Mutation Taster		=87/13	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3765310; hg19: chr6-24503597;