Genetic Variant ALDH5A1:c.-109C>T (chr6-24494888-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The ENST00000491546(ALDH5A1):c.-109C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,174,042 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0074 ( 11 hom., cov: 33)

Exomes 𝑓: 0.00069 ( 4 hom. )

Consequence

ALDH5A1
ENST00000491546 5_prime_UTR

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.0850

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: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.55).

BP6

Variant 6-24494888-C-T is Benign according to our data. Variant chr6-24494888-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1199105.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00737 (1122/152304) while in subpopulation AFR AF = 0.0253 (1052/41572). AF 95% confidence interval is 0.024. There are 11 homozygotes in GnomAd4. There are 542 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position FAILED quality control check.

BS2

High Homozygotes in GnomAd4 at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3 link	c.-109C>T		upstream_gene_variant		ENST00000357578.8	NP_001071.1	P51649-1X5DQN2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8 link	c.-109C>T		upstream_gene_variant		1	NM_001080.3	ENSP00000350191.3		P51649-1

Frequencies

GnomAD3 genomes

AF:

0.00738

AC:

1123

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0254

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00340

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:

0.000132

Gnomad OTH

AF:

0.00430

GnomAD4 exome

AF:

0.000686

AC:

701

AN:

1021738

Hom.:

Cov.:

AF XY:

0.000618

AC XY:

300

AN XY:

485198

show subpopulations

Gnomad4 AFR exome

AF:

0.0225

AC:

477

AN:

21234

Gnomad4 AMR exome

AF:

0.00280

AC:

AN:

7864

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

13136

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

24956

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

19540

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

21138

Gnomad4 NFE exome

AF:

0.000170

AC:

148

AN:

870218

Gnomad4 Remaining exome

AF:

0.00127

AC:

AN:

40920

Heterozygous variant carriers

119

149

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00737

AC:

1122

AN:

152304

Hom.:

Cov.:

AF XY:

0.00728

AC XY:

542

AN XY:

74476

show subpopulations

Gnomad4 AFR

AF:

0.0253

AC:

0.0253055

AN:

0.0253055

Gnomad4 AMR

AF:

0.00340

AC:

0.00339736

AN:

0.00339736

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000132

AC:

0.000132333

AN:

0.000132333

Gnomad4 OTH

AF:

0.00425

AC:

0.00425331

AN:

0.00425331

Heterozygous variant carriers

108

162

216

270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00698

Hom.:

Bravo

AF:

0.00808

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Sep 16, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

8.1

DANN

Benign

0.88

Mutation Taster

=299/1

polymorphism

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over