NM_001080.3:c.545C>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_001080.3(ALDH5A1):​c.545C>T​(p.Pro182Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0302 in 1,613,974 control chromosomes in the GnomAD database, including 1,292 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P182V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.029 (100 hom., cov: 32)
  • Exomes 𝑓: 0.030 (1192 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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: Benign. The variant received -17 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
• 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=0.0026880205).
• BP6: Variant 6-24503369-C-T is Benign according to our data. Variant chr6-24503369-C-T is described in ClinVar as Benign. ClinVar VariationId is 128344.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0915 is higher than 0.05.

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>T	p.Pro182Leu	missense	Exon 3 of 10	NP_001071.1
	ALDH5A1	NM_170740.1		c.545C>T	p.Pro182Leu	missense	Exon 3 of 11	NP_733936.1
	ALDH5A1	NM_001368954.1		c.545C>T	p.Pro182Leu	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>T	p.Pro182Leu	missense	Exon 3 of 10	ENSP00000350191.3
	ALDH5A1	ENST00000348925.2	TSL:1	c.545C>T	p.Pro182Leu	missense	Exon 3 of 11	ENSP00000314649.3
	ALDH5A1	ENST00000491546.5	TSL:5	c.461C>T	p.Pro154Leu	missense	Exon 2 of 9	ENSP00000417687.1

Frequencies

GnomAD3 genomes AF: 0.0285 AC: 4336 AN: 152214 Hom.: 99 Cov.: 32

Gnomad AFR AF: 0.0230

Gnomad AMI AF: 0.0866

Gnomad AMR AF: 0.0222

Gnomad ASJ AF: 0.0271

Gnomad EAS AF: 0.0829

Gnomad SAS AF: 0.0998

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0251

Gnomad OTH AF: 0.0287

GnomAD2 exomes AF: 0.0380 AC: 9539 AN: 251096 AF XY: 0.0410

Gnomad AFR exome AF: 0.0206

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.0302

Gnomad EAS exome AF: 0.0803

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0256

Gnomad OTH exome AF: 0.0347

GnomAD4 exome AF: 0.0304 AC: 44435 AN: 1461642 Hom.: 1192 Cov.: 33 AF XY: 0.0324 AC XY: 23590 AN XY: 727118

African (AFR) AF: 0.0251 AC: 840 AN: 33478

American (AMR) AF: 0.0216 AC: 968 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0281 AC: 734 AN: 26136

East Asian (EAS) AF: 0.0962 AC: 3818 AN: 39690

South Asian (SAS) AF: 0.0993 AC: 8560 AN: 86244

European-Finnish (FIN) AF: 0.0216 AC: 1152 AN: 53258

Middle Eastern (MID) AF: 0.0612 AC: 353 AN: 5768

European-Non Finnish (NFE) AF: 0.0233 AC: 25869 AN: 1111962

Other (OTH) AF: 0.0355 AC: 2141 AN: 60390

GnomAD4 genome AF: 0.0285 AC: 4345 AN: 152332 Hom.: 100 Cov.: 32 AF XY: 0.0290 AC XY: 2160 AN XY: 74496

African (AFR) AF: 0.0230 AC: 958 AN: 41584

American (AMR) AF: 0.0222 AC: 340 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0271 AC: 94 AN: 3470

East Asian (EAS) AF: 0.0831 AC: 431 AN: 5184

South Asian (SAS) AF: 0.0988 AC: 477 AN: 4828

European-Finnish (FIN) AF: 0.0162 AC: 172 AN: 10618

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0251 AC: 1706 AN: 68024

Other (OTH) AF: 0.0345 AC: 73 AN: 2116

Alfa AF: 0.0283 Hom.: 287

Bravo AF: 0.0275

TwinsUK AF: 0.0208 AC: 77

ALSPAC AF: 0.0246 AC: 95

ESP6500AA AF: 0.0241 AC: 106

ESP6500EA AF: 0.0273 AC: 235

ExAC AF: 0.0401 AC: 4866

Asia WGS AF: 0.109 AC: 379 AN: 3478

EpiCase AF: 0.0281

EpiControl AF: 0.0276

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	2	Succinate-semialdehyde dehydrogenase deficiency (2)
-	-	1	ALDH5A1-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0027	T
MetaSVM	Uncertain	0.27	D
MutationAssessor	Benign	1.4	L
PhyloP100		5.9
PrimateAI	Benign	0.28	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.30
Sift	Benign	0.11	T
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.22
MPC		0.68
ClinPred		0.024	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.34
gMVP		0.72
Mutation Taster		=91/9	polymorphism (auto)

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: rs3765310; hg19: chr6-24503597; COSMIC: COSV62373886;