rs1054899

Variant names:

• chr6-24533965-C-A
• rs1054899
• NM_001080.3:c.*253C>A

Your query was ambiguous. Multiple possible variants found:

• chr6-24533965-C-A
• chr6-24533965-C-G

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.*253C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.361 in 443,856 control chromosomes in the GnomAD database, including 31,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (14512 hom., cov: 32)
  • Exomes 𝑓: 0.33 (17206 hom.)
• Consequence: ALDH5A1 NM_170740.1 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.278
• Publications: 19 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=-0.83).
• BP6: Variant 6-24533965-C-A is Benign according to our data. Variant chr6-24533965-C-A is described in ClinVar as Benign. ClinVar VariationId is 356145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.626 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH5A1	NM_001080.3	MANE Select	c.*253C>A		3_prime_UTR	Exon 10 of 10	NP_001071.1
	ALDH5A1	NM_170740.1		c.*253C>A		3_prime_UTR	Exon 11 of 11	NP_733936.1
	ALDH5A1	NM_001368954.1		c.*253C>A		3_prime_UTR	Exon 9 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.*253C>A		3_prime_UTR	Exon 10 of 10	ENSP00000350191.3
	ALDH5A1	ENST00000348925.2	TSL:1	c.*253C>A		3_prime_UTR	Exon 11 of 11	ENSP00000314649.3
	ALDH5A1	ENST00000859835.1		c.*253C>A		3_prime_UTR	Exon 10 of 10	ENSP00000529894.1

Frequencies

GnomAD3 genomes AF: 0.412 AC: 62604 AN: 151948 Hom.: 14479 Cov.: 32

Gnomad AFR AF: 0.632

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.319

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.306

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.344

Gnomad OTH AF: 0.393

GnomAD4 exome AF: 0.334 AC: 97540 AN: 291790 Hom.: 17206 Cov.: 3 AF XY: 0.332 AC XY: 52384 AN XY: 157816

African (AFR) AF: 0.635 AC: 5384 AN: 8484

American (AMR) AF: 0.266 AC: 3585 AN: 13472

Ashkenazi Jewish (ASJ) AF: 0.311 AC: 2553 AN: 8218

East Asian (EAS) AF: 0.147 AC: 2375 AN: 16126

South Asian (SAS) AF: 0.311 AC: 12936 AN: 41608

European-Finnish (FIN) AF: 0.379 AC: 5035 AN: 13270

Middle Eastern (MID) AF: 0.411 AC: 484 AN: 1178

European-Non Finnish (NFE) AF: 0.343 AC: 59492 AN: 173494

Other (OTH) AF: 0.357 AC: 5696 AN: 15940

GnomAD4 genome AF: 0.412 AC: 62695 AN: 152066 Hom.: 14512 Cov.: 32 AF XY: 0.407 AC XY: 30247 AN XY: 74338

African (AFR) AF: 0.633 AC: 26219 AN: 41450

American (AMR) AF: 0.296 AC: 4524 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.319 AC: 1108 AN: 3470

East Asian (EAS) AF: 0.173 AC: 893 AN: 5172

South Asian (SAS) AF: 0.306 AC: 1476 AN: 4822

European-Finnish (FIN) AF: 0.373 AC: 3952 AN: 10586

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.344 AC: 23377 AN: 67964

Other (OTH) AF: 0.390 AC: 824 AN: 2114

Alfa AF: 0.361 Hom.: 28260

Bravo AF: 0.417

Asia WGS AF: 0.283 AC: 985 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	6.3
DANN	Benign	0.46
PhyloP100		0.28
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1054899; hg19: chr6-24534193;