rs1054899

chr6-24533965-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080.3(ALDH5A1):c.*253C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 443,856 control chromosomes in the GnomAD database, including 31,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14512 hom., cov: 32)
  • Exomes 𝑓: 0.33 (17206 hom.)
• Consequence: ALDH5A1 NM_001080.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.278

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 6-24533965-C-A is Benign according to our data. Variant chr6-24533965-C-A is described in ClinVar as [Benign]. Clinvar id is 356145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.626 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.*253C>A		3_prime_UTR_variant	10/10	ENST00000357578.8
ALDH5A1	NM_001368954.1	c.*253C>A		3_prime_UTR_variant	9/9
ALDH5A1	NM_170740.1	c.*253C>A		3_prime_UTR_variant	11/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.*253C>A		3_prime_UTR_variant	10/10	1	NM_001080.3	P1
ALDH5A1	ENST00000348925.2	c.*253C>A		3_prime_UTR_variant	11/11	1
ALDH5A1	ENST00000672352.1	c.*253C>A		3_prime_UTR_variant	9/9
ALDH5A1	ENST00000672652.1	c.*1135C>A		3_prime_UTR_variant, NMD_transcript_variant	10/10

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62604 AN: 151948 Hom.: 14479 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.334 AC: 97540 AN: 291790 Hom.: 17206 Cov.: 3 AF XY: 0.332 AC XY: 52384 AN XY: 157816

Gnomad4 AFR exome AF: 0.635

Gnomad4 AMR exome AF: 0.266

Gnomad4 ASJ exome AF: 0.311

Gnomad4 EAS exome AF: 0.147

Gnomad4 SAS exome AF: 0.311

Gnomad4 FIN exome AF: 0.379

Gnomad4 NFE exome AF: 0.343

Gnomad4 OTH exome AF: 0.357

GnomAD4 genome AF: 0.412 AC: 62695 AN: 152066 Hom.: 14512 Cov.: 32 AF XY: 0.407 AC XY: 30247 AN XY: 74338

Gnomad4 AFR AF: 0.633

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.319

Gnomad4 EAS AF: 0.173

Gnomad4 SAS AF: 0.306

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.344

Gnomad4 OTH AF: 0.390

Alfa AF: 0.346 Hom.: 16204

Bravo AF: 0.417

Asia WGS AF: 0.283 AC: 985 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2018

- -

Succinate-semialdehyde dehydrogenase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	6.3
Dann	Benign	0.46
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs1054899; hg19: chr6-24534193;