Genetic Variant ALDH5A1:p.Ala56Ala (chr6-24495164-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_001080.3(ALDH5A1):c.168G>T(p.Ala56Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000762 in 1,312,226 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. A56A) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.6e-7 ( 0 hom. )

Consequence

ALDH5A1
NM_001080.3 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.884

Publications

0 publications found

Variant links:

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 links:

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]

GPLD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.66).

BP7

Synonymous conserved (PhyloP=-0.884 with no splicing effect.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALDH5A1	NM_001080.3	MANE Select	c.168G>T	p.Ala56Ala	synonymous	Exon 1 of 10	NP_001071.1
ALDH5A1	NM_170740.1		c.168G>T	p.Ala56Ala	synonymous	Exon 1 of 11	NP_733936.1
ALDH5A1	NM_001368954.1		c.168G>T	p.Ala56Ala	synonymous	Exon 1 of 9	NP_001355883.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.168G>T	p.Ala56Ala	synonymous	Exon 1 of 10	ENSP00000350191.3
ALDH5A1	ENST00000348925.2	TSL:1	c.168G>T	p.Ala56Ala	synonymous	Exon 1 of 11	ENSP00000314649.3
ALDH5A1	ENST00000491546.5	TSL:5	c.168G>T	p.Ala56Ala	synonymous	Exon 1 of 9	ENSP00000417687.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.62e-7

AC:

AN:

1312226

Hom.:

Cov.:

AF XY:

0.00000155

AC XY:

AN XY:

646736

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26242

American (AMR)

AF:

0.00

AC:

AN:

25710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22482

East Asian (EAS)

AF:

0.00

AC:

AN:

29082

South Asian (SAS)

AF:

0.0000141

AC:

AN:

70970

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32680

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3864

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1046906

Other (OTH)

AF:

0.00

AC:

AN:

54290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.66

CADD

Benign

7.2

(source)

DANN

Benign

0.84

PhyloP100

-0.88

PromoterAI

-0.14

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over