rs1054899

Variant names:

• chr6-24533965-C-A
• rs1054899
• NM_001080.3:c.*253C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-24533965-C-A
• chr6-24533965-C-G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 19 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• 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 rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.*253C>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.*253C>A		3_prime_UTR_variant	Exon 11 of 11		NP_733936.1
ALDH5A1	NM_001368954.1	c.*253C>A		3_prime_UTR_variant	Exon 9 of 9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.*253C>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_001080.3	ENSP00000350191.3

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

African (AFR) AF: 0.635 AC: 5384 AN: 8484

American (AMR) AF: 0.266 AC: 3585 AN: 13472

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 2553 AN: 8218

East Asian (EAS) AF: 0.147 AC: 2375 AN: 16126

South Asian (SAS) AF: 0.311 AC: 12936 AN: 41608

European-Finnish (FIN) AF: 0.379 AC: 5035 AN: 13270

Middle Eastern (MID) AF: 0.411 AC: 484 AN: 1178

European-Non Finnish (NFE) AF: 0.343 AC: 59492 AN: 173494

Other (OTH) AF: 0.357 AC: 5696 AN: 15940

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

African (AFR) AF: 0.633 AC: 26219 AN: 41450

American (AMR) AF: 0.296 AC: 4524 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1108 AN: 3470

East Asian (EAS) AF: 0.173 AC: 893 AN: 5172

South Asian (SAS) AF: 0.306 AC: 1476 AN: 4822

European-Finnish (FIN) AF: 0.373 AC: 3952 AN: 10586

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23377 AN: 67964

Other (OTH) AF: 0.390 AC: 824 AN: 2114

Alfa AF: 0.361 Hom.: 28260

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

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Succinate-semialdehyde dehydrogenase deficiency Benign:1

Jan 12, 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
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.46
PhyloP100		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	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: rs1054899; hg19: chr6-24534193;