ENST00000474784.5:n.239+220G>C

Variant names:

• chr6-24494747-C-G
• rs2744575
• ENST00000474784.5:n.239+220G>C

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+220G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.327 in 361,032 control chromosomes in the GnomAD database, including 20,384 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.34 (8971 hom., cov: 32)
  • Exomes 𝑓: 0.32 (11413 hom.)
• Consequence: GPLD1 ENST00000474784.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.140
• Publications: 7 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=-0.76).
• BP6: Variant 6-24494747-C-G is Benign according to our data. Variant chr6-24494747-C-G is described in ClinVar as Benign. ClinVar VariationId is 1281626.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.375 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH5A1	NM_001080.3	c.-250C>G		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.-250C>G		upstream_gene_variant		1	NM_001080.3	ENSP00000350191.3

Frequencies

GnomAD3 genomes AF: 0.337 AC: 51137 AN: 151964 Hom.: 8957 Cov.: 32

Gnomad AFR AF: 0.380

Gnomad AMI AF: 0.422

Gnomad AMR AF: 0.232

Gnomad ASJ AF: 0.293

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.286

Gnomad FIN AF: 0.332

Gnomad MID AF: 0.271

Gnomad NFE AF: 0.351

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.320 AC: 66930 AN: 208952 Hom.: 11413 AF XY: 0.319 AC XY: 33794 AN XY: 105792

African (AFR) AF: 0.370 AC: 2154 AN: 5826

American (AMR) AF: 0.227 AC: 1297 AN: 5722

Ashkenazi Jewish (ASJ) AF: 0.277 AC: 2059 AN: 7440

East Asian (EAS) AF: 0.190 AC: 3508 AN: 18426

South Asian (SAS) AF: 0.281 AC: 575 AN: 2048

European-Finnish (FIN) AF: 0.329 AC: 5503 AN: 16744

Middle Eastern (MID) AF: 0.222 AC: 242 AN: 1088

European-Non Finnish (NFE) AF: 0.342 AC: 47270 AN: 138158

Other (OTH) AF: 0.320 AC: 4322 AN: 13500

GnomAD4 genome AF: 0.337 AC: 51200 AN: 152080 Hom.: 8971 Cov.: 32 AF XY: 0.329 AC XY: 24487 AN XY: 74352

African (AFR) AF: 0.380 AC: 15767 AN: 41500

American (AMR) AF: 0.232 AC: 3544 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.293 AC: 1016 AN: 3468

East Asian (EAS) AF: 0.192 AC: 993 AN: 5162

South Asian (SAS) AF: 0.285 AC: 1377 AN: 4830

European-Finnish (FIN) AF: 0.332 AC: 3508 AN: 10582

Middle Eastern (MID) AF: 0.274 AC: 80 AN: 292

European-Non Finnish (NFE) AF: 0.351 AC: 23874 AN: 67942

Other (OTH) AF: 0.311 AC: 657 AN: 2112

Alfa AF: 0.352 Hom.: 1169

Bravo AF: 0.332

Asia WGS AF: 0.255 AC: 891 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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	6.2
DANN	Benign	0.74
PhyloP100		-0.14
PromoterAI		-0.099	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2744575; hg19: chr6-24494975;