6-24503362-C-T

Variant names:

• chr6-24503362-C-T
• rs2760118
• NM_001080.3:c.538C>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.538C>T​(p.His180Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.337 in 1,613,672 control chromosomes in the GnomAD database, including 94,205 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. H180R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.35 (9759 hom., cov: 33)
  • Exomes 𝑓: 0.34 (84446 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.902
• Publications: 56 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 -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 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=2.1404028E-4).
• BP6: Variant 6-24503362-C-T is Benign according to our data. Variant chr6-24503362-C-T is described in ClinVar as Benign. ClinVar VariationId is 128343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.442 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.538C>T	p.His180Tyr	missense	Exon 3 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.538C>T	p.His180Tyr	missense	Exon 3 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.538C>T	p.His180Tyr	missense	Exon 3 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.538C>T	p.His180Tyr	missense	Exon 3 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000348925.2	TSL:1	c.538C>T	p.His180Tyr	missense	Exon 3 of 11	ENSP00000314649.3	P51649-2
	ALDH5A1	ENST00000859838.1		c.481C>T	p.His161Tyr	missense	Exon 3 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes AF: 0.348 AC: 52939 AN: 151964 Hom.: 9736 Cov.: 33

Gnomad AFR AF: 0.447

Gnomad AMI AF: 0.477

Gnomad AMR AF: 0.237

Gnomad ASJ AF: 0.244

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.314

Gnomad FIN AF: 0.323

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.337

Gnomad OTH AF: 0.324

GnomAD2 exomes AF: 0.310 AC: 77832 AN: 250958 AF XY: 0.310

Gnomad AFR exome AF: 0.448

Gnomad AMR exome AF: 0.211

Gnomad ASJ exome AF: 0.244

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.336

Gnomad NFE exome AF: 0.338

Gnomad OTH exome AF: 0.303

GnomAD4 exome AF: 0.336 AC: 491584 AN: 1461590 Hom.: 84446 Cov.: 49 AF XY: 0.335 AC XY: 243236 AN XY: 727100

African (AFR) AF: 0.448 AC: 14997 AN: 33476

American (AMR) AF: 0.217 AC: 9689 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 6378 AN: 26134

East Asian (EAS) AF: 0.196 AC: 7771 AN: 39698

South Asian (SAS) AF: 0.319 AC: 27484 AN: 86236

European-Finnish (FIN) AF: 0.338 AC: 18006 AN: 53252

Middle Eastern (MID) AF: 0.247 AC: 1426 AN: 5766

European-Non Finnish (NFE) AF: 0.347 AC: 385907 AN: 1111926

Other (OTH) AF: 0.330 AC: 19926 AN: 60384

GnomAD4 genome AF: 0.349 AC: 53015 AN: 152082 Hom.: 9759 Cov.: 33 AF XY: 0.341 AC XY: 25347 AN XY: 74356

African (AFR) AF: 0.447 AC: 18526 AN: 41454

American (AMR) AF: 0.237 AC: 3619 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.244 AC: 848 AN: 3470

East Asian (EAS) AF: 0.192 AC: 993 AN: 5172

South Asian (SAS) AF: 0.313 AC: 1512 AN: 4830

European-Finnish (FIN) AF: 0.323 AC: 3420 AN: 10588

Middle Eastern (MID) AF: 0.262 AC: 77 AN: 294

European-Non Finnish (NFE) AF: 0.337 AC: 22898 AN: 67978

Other (OTH) AF: 0.327 AC: 689 AN: 2106

Alfa AF: 0.331 Hom.: 39562

Bravo AF: 0.347

TwinsUK AF: 0.351 AC: 1303

ALSPAC AF: 0.354 AC: 1366

ESP6500AA AF: 0.440 AC: 1937

ESP6500EA AF: 0.336 AC: 2891

ExAC AF: 0.319 AC: 38704

Asia WGS AF: 0.279 AC: 972 AN: 3478

EpiCase AF: 0.314

EpiControl AF: 0.313

ClinVar

ClinVar submissions

Significance: 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	0.053
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.8
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.00021	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N
PhyloP100		0.90
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.13
Sift	Benign	0.13	T
Sift4G	Benign	0.11	T
Polyphen		0.0	B
Vest4		0.068
MPC		0.31
ClinPred		0.0016	T
GERP RS		-0.044
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.25
gMVP		0.55
Mutation Taster		=99/1	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: rs2760118; hg19: chr6-24503590; COSMIC: COSV62373018;