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: Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.*1268C>A		3_prime_UTR	Exon 10 of 10	NP_001071.1	X5DQN2
	ALDH5A1	NM_170740.1		c.*1268C>A		3_prime_UTR	Exon 11 of 11	NP_733936.1	X5D299
	ALDH5A1	NM_001368954.1		c.*1268C>A		3_prime_UTR	Exon 9 of 9	NP_001355883.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.*1268C>A		3_prime_UTR	Exon 10 of 10	ENSP00000350191.3	P51649-1
	ALDH5A1	ENST00000859835.1		c.*1268C>A		3_prime_UTR	Exon 10 of 10	ENSP00000529894.1
	ALDH5A1	ENST00000859837.1		c.*1268C>A		3_prime_UTR	Exon 9 of 9	ENSP00000529896.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Succinate-semialdehyde dehydrogenase deficiency (1)

Computational scores

Source: dbNSFP v4.9

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;