rs2275272

Variant names:

Variant summary

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

The NM_002860.4(ALDH18A1):c.896C>T(p.Thr299Ile) variant causes a missense change. The variant allele was found at a frequency of 0.117 in 1,613,818 control chromosomes in the GnomAD database, including 11,755 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.10 ( 927 hom., cov: 32)

Exomes 𝑓: 0.12 ( 10828 hom. )

Consequence

ALDH18A1
NM_002860.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 6.27

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 (MetaRNN=0.0019159019).

BP6

Variant 10-95628405-G-A is Benign according to our data. Variant chr10-95628405-G-A is described in ClinVar as [Benign]. Clinvar id is 258827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95628405-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH18A1	NM_002860.4 link	c.896C>T	p.Thr299Ile	missense_variant	Exon 8 of 18	ENST00000371224.7	NP_002851.2	P54886-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ALDH18A1	ENST00000371224.7 link	c.896C>T	p.Thr299Ile	missense_variant	Exon 8 of 18	1	NM_002860.4	ENSP00000360268.2	P54886-1
ALDH18A1	ENST00000371221.3 link	c.890C>T	p.Thr297Ile	missense_variant	Exon 8 of 18	1		ENSP00000360265.3	P54886-2
ALDH18A1	ENST00000489386.1 link	n.261C>T		non_coding_transcript_exon_variant	Exon 2 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.101

AC:

15433

AN:

152096

Hom.:

926

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0475

Gnomad AMI

AF:

0.0680

Gnomad AMR

AF:

0.0976

Gnomad ASJ

AF:

0.202

Gnomad EAS

AF:

0.0406

Gnomad SAS

AF:

0.0599

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.204

Gnomad NFE

AF:

0.130

Gnomad OTH

AF:

0.123

GnomAD3 exomes

AF:

0.105

AC:

26433

AN:

251388

Hom.:

1610

AF XY:

0.107

AC XY:

14570

AN XY:

135878

show subpopulations

Gnomad AFR exome

AF:

0.0429

Gnomad AMR exome

AF:

0.0678

Gnomad ASJ exome

AF:

0.194

Gnomad EAS exome

AF:

0.0411

Gnomad SAS exome

AF:

0.0634

Gnomad FIN exome

AF:

0.149

Gnomad NFE exome

AF:

0.130

Gnomad OTH exome

AF:

0.128

GnomAD4 exome

AF:

0.119

AC:

173221

AN:

1461604

Hom.:

10828

Cov.:

AF XY:

0.118

AC XY:

85718

AN XY:

727108

show subpopulations

Gnomad4 AFR exome

AF:

0.0426

Gnomad4 AMR exome

AF:

0.0712

Gnomad4 ASJ exome

AF:

0.185

Gnomad4 EAS exome

AF:

0.0373

Gnomad4 SAS exome

AF:

0.0643

Gnomad4 FIN exome

AF:

0.150

Gnomad4 NFE exome

AF:

0.127

Gnomad4 OTH exome

AF:

0.117

GnomAD4 genome

AF:

0.101

AC:

15432

AN:

152214

Hom.:

927

Cov.:

AF XY:

0.101

AC XY:

7529

AN XY:

74426

show subpopulations

Gnomad4 AFR

AF:

0.0474

Gnomad4 AMR

AF:

0.0974

Gnomad4 ASJ

AF:

0.202

Gnomad4 EAS

AF:

0.0408

Gnomad4 SAS

AF:

0.0601

Gnomad4 FIN

AF:

0.149

Gnomad4 NFE

AF:

0.130

Gnomad4 OTH

AF:

0.123

Alfa

AF:

0.126

Hom.:

3302

Bravo

AF:

0.0963

TwinsUK

AF:

0.131

AC:

485

ALSPAC

AF:

0.125

AC:

483

ESP6500AA

AF:

0.0527

AC:

232

ESP6500EA

AF:

0.126

AC:

1084

ExAC

AF:

0.103

AC:

12503

Asia WGS

AF:

0.0410

AC:

142

AN:

3478

EpiCase

AF:

0.139

EpiControl

AF:

0.141

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 03, 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. -

ALDH18A1-related de Barsy syndrome

Benign:2

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. -

Jul 14, 2021

Genome-Nilou Lab

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

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

T;.

Eigen

Uncertain

0.20

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.97

D;D

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.4

L;.

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-2.0

N;N

REVEL

Uncertain

0.31

Sift

Benign

0.056

T;D

Sift4G

Benign

0.099

T;T

Polyphen

0.051

B;B

Vest4

0.21

MPC

1.7

ClinPred

0.018

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.35

gMVP

0.82

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