10-95606350-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002860.4(ALDH18A1):c.*412T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.34 in 1,012,226 control chromosomes in the GnomAD database, including 61,327 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.28 (6783 hom., cov: 33)
  • Exomes 𝑓: 0.35 (54544 hom.)
• Consequence: ALDH18A1 NM_002860.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.117

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 10-95606350-A-G is Benign according to our data. Variant chr10-95606350-A-G is described in ClinVar as [Benign]. Clinvar id is 301749.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH18A1	NM_002860.4	c.*412T>C		3_prime_UTR_variant	18/18	ENST00000371224.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.*412T>C		3_prime_UTR_variant	18/18	1	NM_002860.4	P3
ALDH18A1	ENST00000371221.3	c.*412T>C		3_prime_UTR_variant	18/18	1		A1

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42116 AN: 152072 Hom.: 6791 Cov.: 33

Gnomad AFR AF: 0.139

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.217

Gnomad EAS AF: 0.0441

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.352 AC: 302489 AN: 860036 Hom.: 54544 Cov.: 29 AF XY: 0.352 AC XY: 140309 AN XY: 398662

Gnomad4 AFR exome AF: 0.119

Gnomad4 AMR exome AF: 0.421

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.0411

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.301

Gnomad4 NFE exome AF: 0.364

Gnomad4 OTH exome AF: 0.317

GnomAD4 genome AF: 0.277 AC: 42098 AN: 152190 Hom.: 6783 Cov.: 33 AF XY: 0.275 AC XY: 20462 AN XY: 74400

Gnomad4 AFR AF: 0.139

Gnomad4 AMR AF: 0.396

Gnomad4 ASJ AF: 0.217

Gnomad4 EAS AF: 0.0436

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.316

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.257

Alfa AF: 0.335 Hom.: 3464

Bravo AF: 0.280

Asia WGS AF: 0.128 AC: 449 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

ALDH18A1-related de Barsy syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	6.2
Dann	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs8758; hg19: chr10-97366107;