rs765561257

Variant names:

• chr6-24495274-G-A
• rs765561257
• NM_001080.3:c.278G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-24495274-G-A
• chr6-24495274-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP2

The NM_001080.3(ALDH5A1):​c.278G>A​(p.Cys93Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C93F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.17
• Publications: 10 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]

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

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr6-24495274-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 449408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 55 curated pathogenic missense variants (we use a threshold of 10). The gene has 13 curated benign missense variants. Gene score misZ: 0.73405 (below the threshold of 3.09). Trascript score misZ: 0.28023 (below the threshold of 3.09). GenCC associations: The gene is linked to succinic semialdehyde dehydrogenase deficiency.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.278G>A	p.Cys93Tyr	missense	Exon 1 of 10	NP_001071.1
	ALDH5A1	NM_170740.1		c.278G>A	p.Cys93Tyr	missense	Exon 1 of 11	NP_733936.1
	ALDH5A1	NM_001368954.1		c.278G>A	p.Cys93Tyr	missense	Exon 1 of 9	NP_001355883.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.278G>A	p.Cys93Tyr	missense	Exon 1 of 10	ENSP00000350191.3
	ALDH5A1	ENST00000348925.2	TSL:1	c.278G>A	p.Cys93Tyr	missense	Exon 1 of 11	ENSP00000314649.3
	ALDH5A1	ENST00000491546.5	TSL:5	c.278G>A	p.Cys93Tyr	missense	Exon 1 of 9	ENSP00000417687.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 127784 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1380650 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 681260

African (AFR) AF: 0.00 AC: 0 AN: 31448

American (AMR) AF: 0.00 AC: 0 AN: 35656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25102

East Asian (EAS) AF: 0.00 AC: 0 AN: 35682

South Asian (SAS) AF: 0.00 AC: 0 AN: 79098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33452

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078290

Other (OTH) AF: 0.00 AC: 0 AN: 57690

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	22
DANN	Benign	0.94
DEOGEN2	Uncertain	0.49	T
Eigen	Uncertain	0.20
Eigen_PC	Benign	0.057
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		3.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.016	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.44
MutPred		0.66		Gain of MoRF binding (P = 0.0714)
MVP		0.96
MPC		0.53
ClinPred		0.88	D
GERP RS		2.2
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.86
gMVP		0.85
Mutation Taster		=17/83	disease causing

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: rs765561257; hg19: chr6-24495502;