rs1053905

chr10-95606607-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002860.4(ALDH18A1):c.*155G>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 0.495 in 1,579,346 control chromosomes in the GnomAD database, including 203,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (15315 hom., cov: 32)
  • Exomes 𝑓: 0.50 (188414 hom.)
• Consequence: ALDH18A1 NM_002860.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0270

Genes affected

ALDH18A1 (HGNC:9722): (aldehyde dehydrogenase 18 family member A1) This gene is a member of the aldehyde dehydrogenase family and encodes a bifunctional ATP- and NADPH-dependent mitochondrial enzyme with both gamma-glutamyl kinase and gamma-glutamyl phosphate reductase activities. The encoded protein catalyzes the reduction of glutamate to delta1-pyrroline-5-carboxylate, a critical step in the de novo biosynthesis of proline, ornithine and arginine. Mutations in this gene lead to hyperammonemia, hypoornithinemia, hypocitrullinemia, hypoargininemia and hypoprolinemia and may be associated with neurodegeneration, cataracts and connective tissue diseases. Alternatively spliced transcript variants, encoding different isoforms, have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-95606607-C-T is Benign according to our data. Variant chr10-95606607-C-T is described in ClinVar as [Benign]. Clinvar id is 301753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH18A1	NM_002860.4	c.*155G>A		3_prime_UTR_variant	18/18	ENST00000371224.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.*155G>A		3_prime_UTR_variant	18/18	1	NM_002860.4	P3
ALDH18A1	ENST00000371221.3	c.*155G>A		3_prime_UTR_variant	18/18	1		A1

Frequencies

GnomAD3 genomes AF: 0.421 AC: 63902 AN: 151962 Hom.: 15331 Cov.: 32

Gnomad AFR AF: 0.216

Gnomad AMI AF: 0.465

Gnomad AMR AF: 0.526

Gnomad ASJ AF: 0.482

Gnomad EAS AF: 0.0849

Gnomad SAS AF: 0.301

Gnomad FIN AF: 0.510

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.538

Gnomad OTH AF: 0.428

GnomAD4 exome AF: 0.503 AC: 718183 AN: 1427266 Hom.: 188414 Cov.: 40 AF XY: 0.498 AC XY: 352518 AN XY: 707796

Gnomad4 AFR exome AF: 0.201

Gnomad4 AMR exome AF: 0.553

Gnomad4 ASJ exome AF: 0.475

Gnomad4 EAS exome AF: 0.0876

Gnomad4 SAS exome AF: 0.323

Gnomad4 FIN exome AF: 0.519

Gnomad4 NFE exome AF: 0.540

Gnomad4 OTH exome AF: 0.472

GnomAD4 genome AF: 0.420 AC: 63876 AN: 152080 Hom.: 15315 Cov.: 32 AF XY: 0.418 AC XY: 31045 AN XY: 74338

Gnomad4 AFR AF: 0.215

Gnomad4 AMR AF: 0.525

Gnomad4 ASJ AF: 0.482

Gnomad4 EAS AF: 0.0847

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.510

Gnomad4 NFE AF: 0.538

Gnomad4 OTH AF: 0.423

Alfa AF: 0.485 Hom.: 7046

Bravo AF: 0.416

Asia WGS AF: 0.179 AC: 627 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ALDH18A1-related de Barsy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	1.3
Dann	Benign	0.63

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

Publications

LitVar

Other links and lift over

dbSNP: rs1053905; hg19: chr10-97366364; COSMIC: COSV64663279; COSMIC: COSV64663279;