rs144177566

Variant names:

• chr6-24532123-G-A
• rs144177566
• NM_001080.3:c.1348G>A
• ALDH5A1 p.Asp450Asn

Your query was ambiguous. Multiple possible variants found:

• chr6-24532123-G-A
• chr6-24532123-G-C
• chr6-24532123-G-T

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.1348G>A​(p.Asp450Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000375 in 1,614,096 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign 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. D450E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0020 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 1.57
• Publications: 4 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=0.0119740665).
• BP6: Variant 6-24532123-G-A is Benign according to our data. Variant chr6-24532123-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 287090.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00202 (307/152294) while in subpopulation AFR AF = 0.00688 (286/41562). AF 95% confidence interval is 0.00623. There are 2 homozygotes in GnomAd4. There are 142 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.1348G>A	p.Asp450Asn	missense	Exon 9 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.1387G>A	p.Asp463Asn	missense	Exon 10 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.1204G>A	p.Asp402Asn	missense	Exon 8 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.1348G>A	p.Asp450Asn	missense	Exon 9 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.1387G>A	p.Asp463Asn	missense	Exon 10 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.1330G>A	p.Asp444Asn	missense	Exon 10 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152176 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00690

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000541 AC: 136 AN: 251436 AF XY: 0.000316

Gnomad AFR exome AF: 0.00658

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000205 AC: 299 AN: 1461802 Hom.: 0 Cov.: 30 AF XY: 0.000194 AC XY: 141 AN XY: 727202

African (AFR) AF: 0.00624 AC: 209 AN: 33480

American (AMR) AF: 0.000514 AC: 23 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000288 AC: 32 AN: 1111940

Other (OTH) AF: 0.000464 AC: 28 AN: 60392

GnomAD4 genome AF: 0.00202 AC: 307 AN: 152294 Hom.: 2 Cov.: 33 AF XY: 0.00191 AC XY: 142 AN XY: 74468

African (AFR) AF: 0.00688 AC: 286 AN: 41562

American (AMR) AF: 0.000785 AC: 12 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68018

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.000771 Hom.: 0

Bravo AF: 0.00251

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not specified (3)
-	-	2	not provided (2)
-	-	2	Succinate-semialdehyde dehydrogenase deficiency (2)
-	-	1	ALDH5A1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.6
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.87	N
REVEL	Benign	0.20
Sift	Benign	0.26	T
Sift4G	Benign	0.14	T
Varity_R		0.16
gMVP		0.42
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs144177566; hg19: chr6-24532351; COSMIC: COSV62372639;