rs2275272

Variant names:

Variant summary

Our verdict is Benign. The variant received -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

Publications

32 publications found

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 Gene-Disease associations (from GenCC):

cutis laxa, autosomal dominant 3
Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
ALDH18A1-related de Barsy syndrome
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
autosomal recessive complex spastic paraplegia type 9B
Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
P5CS deficiency
Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
hereditary spastic paraplegia 9A
Inheritance: AD, SD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
autosomal dominant complex spastic paraplegia type 9B
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal dominant cutis laxa
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ALDH18A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 258827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Ensembl

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

GnomAD2 exomes

AF:

0.105

AC:

26433

AN:

251388

AF XY:

0.107

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 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

African (AFR)

AF:

0.0426

AC:

1427

AN:

33480

American (AMR)

AF:

0.0712

AC:

3186

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.185

AC:

4846

AN:

26130

East Asian (EAS)

AF:

0.0373

AC:

1482

AN:

39694

South Asian (SAS)

AF:

0.0643

AC:

5550

AN:

86256

European-Finnish (FIN)

AF:

0.150

AC:

8001

AN:

53404

Middle Eastern (MID)

AF:

0.166

AC:

956

AN:

5768

European-Non Finnish (NFE)

AF:

0.127

AC:

140704

AN:

1111762

Other (OTH)

AF:

0.117

AC:

7069

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

8831

17662

26494

35325

44156

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4944

9888

14832

19776

24720

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.101

AC:

15432

AN:

152214

Hom.:

927

Cov.:

AF XY:

0.101

AC XY:

7529

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0474

AC:

1969

AN:

41532

American (AMR)

AF:

0.0974

AC:

1489

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.202

AC:

699

AN:

3466

East Asian (EAS)

AF:

0.0408

AC:

212

AN:

5190

South Asian (SAS)

AF:

0.0601

AC:

290

AN:

4822

European-Finnish (FIN)

AF:

0.149

AC:

1577

AN:

10598

Middle Eastern (MID)

AF:

0.205

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.130

AC:

8815

AN:

68000

Other (OTH)

AF:

0.123

AC:

259

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

701

1402

2104

2805

3506

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.121

Hom.:

5559

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

(source)

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;.

PhyloP100

6.3

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

Mutation Taster

=95/5

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over