10-95606622-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002860.4(ALDH18A1):c.*140C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 1,593,628 control chromosomes in the GnomAD database, including 661 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0079 (105 hom., cov: 32)
  • Exomes 𝑓: 0.0054 (556 hom.)
• Consequence: ALDH18A1 NM_002860.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -2.51

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-95606622-G-A is Benign according to our data. Variant chr10-95606622-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 301754.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH18A1	NM_002860.4	c.*140C>T		3_prime_UTR_variant	18/18	ENST00000371224.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.*140C>T		3_prime_UTR_variant	18/18	1	NM_002860.4	P3
ALDH18A1	ENST00000371221.3	c.*140C>T		3_prime_UTR_variant	18/18	1		A1

Frequencies

GnomAD3 genomes AF: 0.00794 AC: 1209 AN: 152172 Hom.: 107 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00635

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.0112

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000411

Gnomad OTH AF: 0.00575

GnomAD4 exome AF: 0.00537 AC: 7747 AN: 1441338 Hom.: 556 Cov.: 34 AF XY: 0.00520 AC XY: 3724 AN XY: 715880

Gnomad4 AFR exome AF: 0.000576

Gnomad4 AMR exome AF: 0.00763

Gnomad4 ASJ exome AF: 0.000235

Gnomad4 EAS exome AF: 0.150

Gnomad4 SAS exome AF: 0.00649

Gnomad4 FIN exome AF: 0.000213

Gnomad4 NFE exome AF: 0.000167

Gnomad4 OTH exome AF: 0.0123

GnomAD4 genome AF: 0.00791 AC: 1204 AN: 152290 Hom.: 105 Cov.: 32 AF XY: 0.00894 AC XY: 666 AN XY: 74474

Gnomad4 AFR AF: 0.000914

Gnomad4 AMR AF: 0.00648

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.188

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00212 Hom.: 2

Bravo AF: 0.00980

Asia WGS AF: 0.0760 AC: 262 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary spastic paraplegia Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 22, 2016

- -

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	-0.89
Cadd	Benign	0.23
Dann	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs76824727; hg19: chr10-97366379; COSMIC: COSV64663283; COSMIC: COSV64663283;