rs2817220

Variant names:

• chr6-24504993-G-A
• rs2817220
• NM_001080.3:c.726+8G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-24504993-G-A
• chr6-24504993-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_170740.1(ALDH5A1):​c.726+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.252 in 1,612,044 control chromosomes in the GnomAD database, including 53,764 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4736 hom., cov: 33)
  • Exomes 𝑓: 0.25 (49028 hom.)
• Consequence: ALDH5A1 NM_170740.1 splice_region, intron
• Scores: Splicing: ADA: 0.00008610
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.118
• Publications: 12 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]

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-24504993-G-A is Benign according to our data. Variant chr6-24504993-G-A is described in ClinVar as Benign. ClinVar VariationId is 356135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.263 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.726+8G>A		splice_region intron	N/A	NP_001071.1
	ALDH5A1	NM_170740.1		c.726+8G>A		splice_region intron	N/A	NP_733936.1
	ALDH5A1	NM_001368954.1		c.726+8G>A		splice_region intron	N/A	NP_001355883.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	ENST00000357578.8	TSL:1 MANE Select	c.726+8G>A		splice_region intron	N/A	ENSP00000350191.3
	ALDH5A1	ENST00000348925.2	TSL:1	c.726+8G>A		splice_region intron	N/A	ENSP00000314649.3
	ALDH5A1	ENST00000859838.1		c.669+8G>A		splice_region intron	N/A	ENSP00000529897.1

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37124 AN: 152020 Hom.: 4733 Cov.: 33

Gnomad AFR AF: 0.267

Gnomad AMI AF: 0.312

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.0983

Gnomad SAS AF: 0.147

Gnomad FIN AF: 0.279

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.263

Gnomad OTH AF: 0.221

GnomAD2 exomes AF: 0.220 AC: 55283 AN: 251196 AF XY: 0.218

Gnomad AFR exome AF: 0.267

Gnomad AMR exome AF: 0.158

Gnomad ASJ exome AF: 0.173

Gnomad EAS exome AF: 0.100

Gnomad FIN exome AF: 0.281

Gnomad NFE exome AF: 0.262

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.253 AC: 369243 AN: 1459904 Hom.: 49028 Cov.: 33 AF XY: 0.249 AC XY: 180958 AN XY: 726410

African (AFR) AF: 0.257 AC: 8610 AN: 33450

American (AMR) AF: 0.162 AC: 7253 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.176 AC: 4585 AN: 26118

East Asian (EAS) AF: 0.0809 AC: 3209 AN: 39690

South Asian (SAS) AF: 0.151 AC: 13011 AN: 86208

European-Finnish (FIN) AF: 0.282 AC: 15016 AN: 53298

Middle Eastern (MID) AF: 0.112 AC: 646 AN: 5760

European-Non Finnish (NFE) AF: 0.272 AC: 302380 AN: 1110336

Other (OTH) AF: 0.241 AC: 14533 AN: 60322

GnomAD4 genome AF: 0.244 AC: 37171 AN: 152140 Hom.: 4736 Cov.: 33 AF XY: 0.239 AC XY: 17763 AN XY: 74380

African (AFR) AF: 0.267 AC: 11069 AN: 41480

American (AMR) AF: 0.173 AC: 2646 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 637 AN: 3472

East Asian (EAS) AF: 0.0987 AC: 511 AN: 5176

South Asian (SAS) AF: 0.147 AC: 709 AN: 4822

European-Finnish (FIN) AF: 0.279 AC: 2952 AN: 10584

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.263 AC: 17857 AN: 67994

Other (OTH) AF: 0.220 AC: 465 AN: 2112

Alfa AF: 0.245 Hom.: 7485

Bravo AF: 0.239

Asia WGS AF: 0.122 AC: 428 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Succinate-semialdehyde dehydrogenase deficiency (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.80
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000086
dbscSNV1_RF	Benign	0.0
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

Other links and lift over

dbSNP: rs2817220; hg19: chr6-24505221; COSMIC: COSV62372795;