rs10882640

Variant names:

• chr10-95610182-C-T
• rs10882640
• NM_002860.4:c.2206+15G>A

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.2206+15G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.454 in 1,612,192 control chromosomes in the GnomAD database, including 174,439 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.39 (12959 hom., cov: 31)
  • Exomes 𝑓: 0.46 (161480 hom.)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.231

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=-0.81).
• BP6: Variant 10-95610182-C-T is Benign according to our data. Variant chr10-95610182-C-T is described in ClinVar as [Benign]. Clinvar id is 258825.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95610182-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.488 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH18A1	NM_002860.4	c.2206+15G>A		intron_variant	Intron 17 of 17	ENST00000371224.7	NP_002851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.2206+15G>A		intron_variant	Intron 17 of 17	1	NM_002860.4	ENSP00000360268.2
ALDH18A1	ENST00000371221.3	c.2200+15G>A		intron_variant	Intron 17 of 17	1		ENSP00000360265.3

Frequencies

GnomAD3 genomes AF: 0.387 AC: 58801 AN: 151956 Hom.: 12971 Cov.: 31

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.442

Gnomad AMR AF: 0.498

Gnomad ASJ AF: 0.427

Gnomad EAS AF: 0.0844

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.472

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.489

Gnomad OTH AF: 0.392

GnomAD3 exomes AF: 0.419 AC: 105115 AN: 250954 Hom.: 24311 AF XY: 0.416 AC XY: 56487 AN XY: 135648

Gnomad AFR exome AF: 0.194

Gnomad AMR exome AF: 0.536

Gnomad ASJ exome AF: 0.428

Gnomad EAS exome AF: 0.0855

Gnomad SAS exome AF: 0.308

Gnomad FIN exome AF: 0.472

Gnomad NFE exome AF: 0.487

Gnomad OTH exome AF: 0.444

GnomAD4 exome AF: 0.461 AC: 672796 AN: 1460118 Hom.: 161480 Cov.: 33 AF XY: 0.456 AC XY: 331467 AN XY: 726422

Gnomad4 AFR exome AF: 0.187

Gnomad4 AMR exome AF: 0.534

Gnomad4 ASJ exome AF: 0.419

Gnomad4 EAS exome AF: 0.0872

Gnomad4 SAS exome AF: 0.310

Gnomad4 FIN exome AF: 0.477

Gnomad4 NFE exome AF: 0.493

Gnomad4 OTH exome AF: 0.435

GnomAD4 genome AF: 0.387 AC: 58780 AN: 152074 Hom.: 12959 Cov.: 31 AF XY: 0.385 AC XY: 28588 AN XY: 74332

Gnomad4 AFR AF: 0.200

Gnomad4 AMR AF: 0.498

Gnomad4 ASJ AF: 0.427

Gnomad4 EAS AF: 0.0842

Gnomad4 SAS AF: 0.290

Gnomad4 FIN AF: 0.472

Gnomad4 NFE AF: 0.489

Gnomad4 OTH AF: 0.388

Alfa AF: 0.467 Hom.: 13533

Bravo AF: 0.385

Asia WGS AF: 0.173 AC: 607 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ALDH18A1-related de Barsy syndrome Benign:4

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 06, 2016

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 specified Benign:2

Sep 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cutis laxa, autosomal dominant 3 Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive complex spastic paraplegia type 9B Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary spastic paraplegia 9A Benign:1

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.5
DANN	Benign	0.53
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: rs10882640; hg19: chr10-97369939; COSMIC: COSV64662210; COSMIC: COSV64662210;