NM_001080.3:c.1348G>C

Variant names:

• chr6-24532123-G-C
• rs144177566
• NM_001080.3:c.1348G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001080.3(ALDH5A1):​c.1348G>C​(p.Asp450His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D450N) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.57
• Publications: 4 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.23016468).

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.1348G>C	p.Asp450His	missense	Exon 9 of 10	NP_001071.1
	ALDH5A1	NM_170740.1		c.1387G>C	p.Asp463His	missense	Exon 10 of 11	NP_733936.1
	ALDH5A1	NM_001368954.1		c.1204G>C	p.Asp402His	missense	Exon 8 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.1348G>C	p.Asp450His	missense	Exon 9 of 10	ENSP00000350191.3
	ALDH5A1	ENST00000348925.2	TSL:1	c.1387G>C	p.Asp463His	missense	Exon 10 of 11	ENSP00000314649.3
	ALDH5A1	ENST00000491546.5	TSL:5	c.1264G>C	p.Asp422His	missense	Exon 8 of 9	ENSP00000417687.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Oct 24, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The D450H variant in the ALDH5A1 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. This variant is not observed in large population cohorts (Lek et al., 2016). The D450H variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved across species, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret D450H as a variant of uncertain significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	0.00020	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	11
DANN	Benign	0.80
DEOGEN2	Benign	0.40	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.6
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Benign	0.085	T
Sift4G	Benign	0.078	T
Polyphen		0.014	B
Vest4		0.27
MutPred		0.37		Loss of ubiquitination at K448 (P = 0.1423)
MVP		0.86
MPC		0.33
ClinPred		0.44	T
GERP RS		-0.25
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.64
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs144177566; hg19: chr6-24532351;