rs2760118

Positions:

• chr6-24503362-C-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 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. 15/20 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:6
• Conservation: PhyloP100: 0.902

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_001080.3
• 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 id is 128343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-24503362-C-T is described in Lovd as [Benign].
• 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/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.538C>T	p.His180Tyr	missense_variant	3/10	ENST00000357578.8
ALDH5A1	NM_170740.1	c.538C>T	p.His180Tyr	missense_variant	3/11
ALDH5A1	NM_001368954.1	c.538C>T	p.His180Tyr	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.538C>T	p.His180Tyr	missense_variant	3/10	1	NM_001080.3	P1

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

GnomAD3 exomes AF: 0.310 AC: 77832 AN: 250958 Hom.: 12873 AF XY: 0.310 AC XY: 42045 AN XY: 135670

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 SAS exome AF: 0.324

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

Gnomad4 AFR exome AF: 0.448

Gnomad4 AMR exome AF: 0.217

Gnomad4 ASJ exome AF: 0.244

Gnomad4 EAS exome AF: 0.196

Gnomad4 SAS exome AF: 0.319

Gnomad4 FIN exome AF: 0.338

Gnomad4 NFE exome AF: 0.347

Gnomad4 OTH exome AF: 0.330

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

Gnomad4 AFR AF: 0.447

Gnomad4 AMR AF: 0.237

Gnomad4 ASJ AF: 0.244

Gnomad4 EAS AF: 0.192

Gnomad4 SAS AF: 0.313

Gnomad4 FIN AF: 0.323

Gnomad4 NFE AF: 0.337

Gnomad4 OTH AF: 0.327

Alfa AF: 0.323 Hom.: 20168

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 10, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	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. -

Succinate-semialdehyde dehydrogenase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 27, 2018

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

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
MutationTaster	Benign	1.0	P;P;P;P
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs2760118; hg19: chr6-24503590; COSMIC: COSV62373018;