6-24533965-C-G

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080.3(ALDH5A1):​c.*253C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 292,344 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.*253C>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.*253C>G		3_prime_UTR_variant	Exon 11 of 11		NP_733936.1
ALDH5A1	NM_001368954.1	c.*253C>G		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>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 1 AN: 292344 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 158132

African (AFR) AF: 0.000118 AC: 1 AN: 8506

American (AMR) AF: 0.00 AC: 0 AN: 13496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8250

East Asian (EAS) AF: 0.00 AC: 0 AN: 16146

South Asian (SAS) AF: 0.00 AC: 0 AN: 41634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1182

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 173858

Other (OTH) AF: 0.00 AC: 0 AN: 15968

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.7
DANN	Benign	0.39
PhyloP100		0.28
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

Other links and lift over

dbSNP: rs1054899; hg19: chr6-24534193;