6-24495018-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001080.3(ALDH5A1):c.22C>T(p.Arg8Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000978 in 1,329,542 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R8R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: ALDH5A1 NM_001080.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.27

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 6-24495018-C-T is Benign according to our data. Variant chr6-24495018-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1095033.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH5A1	NM_001080.3	c.22C>T	p.Arg8Trp	missense_variant	1/10	ENST00000357578.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.22C>T	p.Arg8Trp	missense_variant	1/10	1	NM_001080.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151952 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000143 AC: 12 AN: 84198 Hom.: 0 AF XY: 0.000144 AC XY: 7 AN XY: 48648

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000254

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000105 AC: 124 AN: 1177590 Hom.: 0 Cov.: 31 AF XY: 0.0000912 AC XY: 52 AN XY: 570130

Gnomad4 AFR exome AF: 0.0000801

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000329

Gnomad4 SAS exome AF: 0.0000279

Gnomad4 FIN exome AF: 0.0000369

Gnomad4 NFE exome AF: 0.000120

Gnomad4 OTH exome AF: 0.0000424

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151952 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74234

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000302

ExAC AF: 0.000116 AC: 13

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Sep 04, 2019

In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Succinate-semialdehyde dehydrogenase deficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 21, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Uncertain	0.067	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.33
FATHMM_MKL	Benign	0.026	N
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.95	D
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.81	L;.;L
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		0.99	D;.;.
Vest4		0.40
MutPred		0.53		Loss of disorder (P = 4e-04);Loss of disorder (P = 4e-04);Loss of disorder (P = 4e-04);
MVP		0.91
MPC		0.68
ClinPred		0.27	T
GERP RS		0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.13
gMVP		0.49

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: rs767601869; hg19: chr6-24495246;