rs1554135746

Variant names:

• chr6-24495296-CGCCGTGCGCGCT-C
• rs1554135746
• NM_001080.3:c.304_315delGTGCGCGCTGCC

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM4

The NM_170740.1(ALDH5A1):​c.304_315delGTGCGCGCTGCC​(p.Val102_Ala105del) variant causes a conservative inframe deletion change. The variant allele was found at a frequency of 0.00000145 in 1,380,862 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. V102V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ALDH5A1 NM_170740.1 conservative_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.19
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_170740.1.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_170740.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.304_315delGTGCGCGCTGCC	p.Val102_Ala105del	conservative_inframe_deletion	Exon 1 of 10	NP_001071.1
	ALDH5A1	NM_170740.1		c.304_315delGTGCGCGCTGCC	p.Val102_Ala105del	conservative_inframe_deletion	Exon 1 of 11	NP_733936.1
	ALDH5A1	NM_001368954.1		c.304_315delGTGCGCGCTGCC	p.Val102_Ala105del	conservative_inframe_deletion	Exon 1 of 9	NP_001355883.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.304_315delGTGCGCGCTGCC	p.Val102_Ala105del	conservative_inframe_deletion	Exon 1 of 10	ENSP00000350191.3
	ALDH5A1	ENST00000348925.2	TSL:1	c.304_315delGTGCGCGCTGCC	p.Val102_Ala105del	conservative_inframe_deletion	Exon 1 of 11	ENSP00000314649.3
	ALDH5A1	ENST00000859838.1		c.304_315delGTGCGCGCTGCC	p.Val102_Ala105del	conservative_inframe_deletion	Exon 1 of 11	ENSP00000529897.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000781 AC: 1 AN: 128100 AF XY: 0.0000143

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000210

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1380862 Hom.: 0 AF XY: 0.00000147 AC XY: 1 AN XY: 681364

African (AFR) AF: 0.00 AC: 0 AN: 31462

American (AMR) AF: 0.00 AC: 0 AN: 35668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25124

East Asian (EAS) AF: 0.00 AC: 0 AN: 35694

South Asian (SAS) AF: 0.00 AC: 0 AN: 79112

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33450

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4222

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078422

Other (OTH) AF: 0.00 AC: 0 AN: 57708

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.2

Splicing

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

Other links and lift over

dbSNP: rs1554135746; hg19: chr6-24495524;