6-24532123-G-C

Position:

• chr6-24532123-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• 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

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 (HGNC:):

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=0.23016468).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.1348G>C	p.Asp450His	missense_variant	9/10	ENST00000357578.8	NP_001071.1
ALDH5A1	NM_170740.1	c.1387G>C	p.Asp463His	missense_variant	10/11		NP_733936.1
ALDH5A1	NM_001368954.1	c.1204G>C	p.Asp402His	missense_variant	8/9		NP_001355883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.1348G>C	p.Asp450His	missense_variant	9/10	1	NM_001080.3	ENSP00000350191.3

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

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Oct 24, 2017

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 v4.3

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;T;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.77
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.2	M;.;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.9	N;N;N
REVEL	Benign	0.27
Sift	Benign	0.085	T;T;T
Sift4G	Benign	0.078	T;T;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs144177566; hg19: chr6-24532351;