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: 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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.538C>T	p.His180Tyr	missense_variant	Exon 3 of 10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.538C>T	p.His180Tyr	missense_variant	Exon 3 of 11		NP_733936.1
ALDH5A1	NM_001368954.1	c.538C>T	p.His180Tyr	missense_variant	Exon 3 of 9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.538C>T	p.His180Tyr	missense_variant	Exon 3 of 10	1	NM_001080.3	ENSP00000350191.3

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 42% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 39. Only high quality variants are reported. -

Aug 10, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

Jul 27, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 12208142, 18505418, 27056292, 19164088, 29895405) -

Jun 11, 2024

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.538C>T (p.His180Tyr) variant is not itself pathogenic but it has been reported in several individuals with succinic semialdehyde dehydrogenase deficiency who also had other pathogenic variants in ALDH5A1 (PMID:38791277, PMID:14635103). It is thought to have an enhancing effect on pathogenic variants present in cis (on the same chromosome). Functional studies have been performed to assess the impact of this variant, including an enzyme activity assay demonstrating that this variant has 83% activity relative to wildtype (PMID:14635103). The overall minor allele frequency for this variant (rs2760118) is approximately 31.537%, including 14,947 homozygotes, with a frequency up to 44.684% in African/African American sub-populations. -

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

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;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.024	N
LIST_S2	Benign	0.51	T;T;T
MetaRNN	Benign	0.00021	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.60	N;.;N
PhyloP100		0.90
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.35	N;N;N
REVEL	Benign	0.13
Sift	Benign	0.13	T;T;T
Sift4G	Benign	0.11	T;T;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;