rs4646829

Variant names:

• chr6-24494776-C-T
• rs4646829
• ENST00000474784.5:n.239+191G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000474784.5(GPLD1):​n.239+191G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0287 in 436,896 control chromosomes in the GnomAD database, including 297 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.036 (189 hom., cov: 33)
  • Exomes 𝑓: 0.025 (108 hom.)
• Consequence: GPLD1 ENST00000474784.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.85
• Publications: 1 publications found

Genes affected

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]

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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 6-24494776-C-T is Benign according to our data. Variant chr6-24494776-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233201.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0763 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.-221C>T		upstream_gene_variant		ENST00000357578.8	NP_001071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH5A1	ENST00000357578.8	c.-221C>T		upstream_gene_variant		1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5441 AN: 152172 Hom.: 187 Cov.: 33

Gnomad AFR AF: 0.0785

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0164

Gnomad ASJ AF: 0.0176

Gnomad EAS AF: 0.00753

Gnomad SAS AF: 0.0310

Gnomad FIN AF: 0.00471

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0229

Gnomad OTH AF: 0.0320

GnomAD4 exome AF: 0.0248 AC: 7069 AN: 284606 Hom.: 108 AF XY: 0.0243 AC XY: 3464 AN XY: 142816

African (AFR) AF: 0.0870 AC: 641 AN: 7366

American (AMR) AF: 0.0162 AC: 104 AN: 6402

Ashkenazi Jewish (ASJ) AF: 0.0174 AC: 144 AN: 8270

East Asian (EAS) AF: 0.0254 AC: 518 AN: 20420

South Asian (SAS) AF: 0.0279 AC: 93 AN: 3330

European-Finnish (FIN) AF: 0.00469 AC: 88 AN: 18782

Middle Eastern (MID) AF: 0.0313 AC: 39 AN: 1248

European-Non Finnish (NFE) AF: 0.0247 AC: 5003 AN: 202388

Other (OTH) AF: 0.0268 AC: 439 AN: 16400

GnomAD4 genome AF: 0.0358 AC: 5449 AN: 152290 Hom.: 189 Cov.: 33 AF XY: 0.0341 AC XY: 2536 AN XY: 74460

African (AFR) AF: 0.0786 AC: 3265 AN: 41554

American (AMR) AF: 0.0164 AC: 251 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0176 AC: 61 AN: 3472

East Asian (EAS) AF: 0.00755 AC: 39 AN: 5168

South Asian (SAS) AF: 0.0308 AC: 149 AN: 4832

European-Finnish (FIN) AF: 0.00471 AC: 50 AN: 10624

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0229 AC: 1557 AN: 68018

Other (OTH) AF: 0.0312 AC: 66 AN: 2116

Alfa AF: 0.0312 Hom.: 7

Bravo AF: 0.0387

Asia WGS AF: 0.0180 AC: 64 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jul 15, 2018

GeneDx

Significance: 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	-0.80
CADD	Benign	2.0
DANN	Benign	0.93
PhyloP100		-1.9
PromoterAI		-0.0052	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4646829; hg19: chr6-24495004;