rs10882640

Positions:

chr10-95610182-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.231

Variant links:

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]

ALDH18A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
ALDH18A1	NM_002860.4 linkuse as main transcript	c.2206+15G>A		intron_variant		ENST00000371224.7	NP_002851.2	P54886-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH18A1	ENST00000371224.7 linkuse as main transcript	c.2206+15G>A		intron_variant		1	NM_002860.4	ENSP00000360268.2		P54886-1
ALDH18A1	ENST00000371221.3 linkuse as main transcript	c.2200+15G>A		intron_variant		1		ENSP00000360265.3		P54886-2

Frequencies

GnomAD3 genomes

AF:

0.387

AC:

58801

AN:

151956

Hom.:

12971

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.456

AC XY:

331467

AN XY:

726422

show subpopulations

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.:

AF XY:

0.385

AC XY:

28588

AN XY:

74332

show subpopulations

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

LINK: link

Submissions by phenotype

ALDH18A1-related de Barsy syndrome

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	Jul 06, 2016	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 29, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Cutis laxa, autosomal dominant 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Autosomal recessive complex spastic paraplegia type 9B

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Hereditary spastic paraplegia 9A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over