rs12190214

Variant names:

• chr6-24534980-C-A
• rs12190214
• NM_001080.3:c.*1268C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001080.3(ALDH5A1):​c.*1268C>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 0.0641 in 152,236 control chromosomes in the GnomAD database, including 437 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.064 (437 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: ALDH5A1 NM_001080.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.496
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 6-24534980-C-A is Benign according to our data. Variant chr6-24534980-C-A is described in ClinVar as Benign. ClinVar VariationId is 356165.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.09 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.*1268C>A		3_prime_UTR_variant	Exon 10 of 10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.*1268C>A		3_prime_UTR_variant	Exon 11 of 11		NP_733936.1
ALDH5A1	NM_001368954.1	c.*1268C>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.*1268C>A		3_prime_UTR_variant	Exon 10 of 10	1	NM_001080.3	ENSP00000350191.3
ALDH5A1	ENST00000672652.1	n.*2150C>A		non_coding_transcript_exon_variant	Exon 10 of 10			ENSP00000500192.1
ALDH5A1	ENST00000672352.1	c.*1268C>A		3_prime_UTR_variant	Exon 9 of 9			ENSP00000500876.1
ALDH5A1	ENST00000672652.1	n.*2150C>A		3_prime_UTR_variant	Exon 10 of 10			ENSP00000500192.1

Frequencies

GnomAD3 genomes AF: 0.0641 AC: 9751 AN: 152118 Hom.: 437 Cov.: 33

Gnomad AFR AF: 0.0197

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.0438

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00712

Gnomad SAS AF: 0.0889

Gnomad FIN AF: 0.104

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0919

Gnomad OTH AF: 0.0622

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.0641 AC: 9752 AN: 152236 Hom.: 437 Cov.: 33 AF XY: 0.0638 AC XY: 4748 AN XY: 74444

African (AFR) AF: 0.0197 AC: 819 AN: 41552

American (AMR) AF: 0.0437 AC: 669 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3472

East Asian (EAS) AF: 0.00714 AC: 37 AN: 5184

South Asian (SAS) AF: 0.0894 AC: 431 AN: 4820

European-Finnish (FIN) AF: 0.104 AC: 1098 AN: 10584

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0919 AC: 6249 AN: 68014

Other (OTH) AF: 0.0616 AC: 130 AN: 2112

Alfa AF: 0.0174 Hom.: 285

Bravo AF: 0.0570

Asia WGS AF: 0.0590 AC: 205 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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	-0.90
CADD	Benign	1.1
DANN	Benign	0.53
PhyloP100		-0.50
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: rs12190214; hg19: chr6-24535208;