6-24495126-C-T

Variant names:

• chr6-24495126-C-T
• rs185042766
• NM_001080.3:c.130C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080.3(ALDH5A1):​c.130C>T​(p.Leu44Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000812 in 1,230,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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: 33)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.340

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]

GPLD1 (HGNC:4459): (glycosylphosphatidylinositol specific phospholipase D1) Many proteins are tethered to the extracellular face of eukaryotic plasma membranes by a glycosylphosphatidylinositol (GPI) anchor. The GPI-anchor is a glycolipid found on many blood cells. The protein encoded by this gene is a GPI degrading enzyme. Glycosylphosphatidylinositol specific phospholipase D1 hydrolyzes the inositol phosphate linkage in proteins anchored by phosphatidylinositol glycans, thereby releasing the attached protein from the plasma membrane. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24167243).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.130C>T	p.Leu44Phe	missense_variant	Exon 1 of 10	ENST00000357578.8	NP_001071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.130C>T	p.Leu44Phe	missense_variant	Exon 1 of 10	1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 8.12e-7 AC: 1 AN: 1230840 Hom.: 0 Cov.: 31 AF XY: 0.00000166 AC XY: 1 AN XY: 601754

Gnomad4 AFR exome AF: 0.0000412

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.067	N
LIST_S2	Benign	0.50	T;T;T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.;N
PrimateAI	Pathogenic	0.80	D
PROVEAN	Benign	-0.88	N;N;N
REVEL	Benign	0.10
Sift	Benign	0.052	T;D;D
Sift4G	Benign	0.094	T;T;T
Polyphen		0.26	B;.;.
Vest4		0.12
MutPred		0.29		Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);Gain of helix (P = 0.0117);
MVP		0.79
MPC		0.46
ClinPred		0.20	T
GERP RS		2.9
Varity_R		0.055
gMVP		0.18

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: rs185042766; hg19: chr6-24495354;