6-24504968-G-T

Variant names:

• chr6-24504968-G-T
• rs62621664
• NM_001080.3:c.709G>T
• ALDH5A1 p.Ala237Ser

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 5P and 20B. PM1 PM5 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080.3(ALDH5A1):​c.709G>T​(p.Ala237Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,614,082 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A237T) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.012 (21 hom., cov: 33)
  • Exomes 𝑓: 0.015 (210 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 9.50
• Publications: 20 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), G2P, Orphanet, ClinGen

ACMG classification

Our verdict: Benign. The variant received -15 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_001080.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-24504968-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 904924.
• 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=0.012225747).
• BP6: Variant 6-24504968-G-T is Benign according to our data. Variant chr6-24504968-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 218854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0121 (1847/152302) while in subpopulation NFE AF = 0.0192 (1303/68032). AF 95% confidence interval is 0.0183. There are 21 homozygotes in GnomAd4. There are 833 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.709G>T	p.Ala237Ser	missense	Exon 4 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.709G>T	p.Ala237Ser	missense	Exon 4 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.709G>T	p.Ala237Ser	missense	Exon 4 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.709G>T	p.Ala237Ser	missense	Exon 4 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.709G>T	p.Ala237Ser	missense	Exon 4 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.652G>T	p.Ala218Ser	missense	Exon 4 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes AF: 0.0121 AC: 1847 AN: 152184 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.0559

Gnomad AMR AF: 0.0124

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0192

Gnomad OTH AF: 0.00957

GnomAD2 exomes AF: 0.0114 AC: 2856 AN: 251372 AF XY: 0.0115

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00714

Gnomad ASJ exome AF: 0.00625

Gnomad EAS exome AF: 0.000272

Gnomad FIN exome AF: 0.00781

Gnomad NFE exome AF: 0.0182

Gnomad OTH exome AF: 0.0145

GnomAD4 exome AF: 0.0145 AC: 21242 AN: 1461780 Hom.: 210 Cov.: 33 AF XY: 0.0144 AC XY: 10476 AN XY: 727198

African (AFR) AF: 0.00278 AC: 93 AN: 33480

American (AMR) AF: 0.00745 AC: 333 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00719 AC: 188 AN: 26136

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39698

South Asian (SAS) AF: 0.00674 AC: 581 AN: 86254

European-Finnish (FIN) AF: 0.00901 AC: 481 AN: 53384

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5768

European-Non Finnish (NFE) AF: 0.0167 AC: 18564 AN: 1111944

Other (OTH) AF: 0.0148 AC: 893 AN: 60392

GnomAD4 genome AF: 0.0121 AC: 1847 AN: 152302 Hom.: 21 Cov.: 33 AF XY: 0.0112 AC XY: 833 AN XY: 74466

African (AFR) AF: 0.00274 AC: 114 AN: 41564

American (AMR) AF: 0.0124 AC: 190 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.0120 AC: 58 AN: 4830

European-Finnish (FIN) AF: 0.00801 AC: 85 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0192 AC: 1303 AN: 68032

Other (OTH) AF: 0.00947 AC: 20 AN: 2112

Alfa AF: 0.0158 Hom.: 103

Bravo AF: 0.0120

Asia WGS AF: 0.00664 AC: 23 AN: 3478

EpiCase AF: 0.0200

EpiControl AF: 0.0187

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.73	D
MutationAssessor	Benign	2.0	M
PhyloP100		9.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.051	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.78
gMVP		0.80
Mutation Taster		=56/44	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

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

Other links and lift over

dbSNP: rs62621664;

hg19: chr6-24505196;

COSMIC: COSV62373527;