rs41291566

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002860.4(ALDH18A1):c.1029T>C(p.Ile343Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.029 in 1,614,066 control chromosomes in the GnomAD database, including 861 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 60 hom., cov: 32)

Exomes 𝑓: 0.030 ( 801 hom. )

Consequence

ALDH18A1
NM_002860.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.456

Publications

6 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 10-95627491-A-G is Benign according to our data. Variant chr10-95627491-A-G is described in ClinVar as Benign. ClinVar VariationId is 258823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.456 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0211 (3215/152248) while in subpopulation NFE AF = 0.0334 (2271/68018). AF 95% confidence interval is 0.0322. There are 60 homozygotes in GnomAd4. There are 1532 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 60 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH18A1	NM_002860.4 link	c.1029T>C	p.Ile343Ile	synonymous_variant	Exon 9 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.1029T>C	p.Ile343Ile	synonymous_variant	Exon 9 of 18	1	NM_002860.4	ENSP00000360268.2	P54886-1
ALDH18A1	ENST00000371221.3 link	c.1023T>C	p.Ile341Ile	synonymous_variant	Exon 9 of 18	1		ENSP00000360265.3	P54886-2
ALDH18A1	ENST00000489386.1 link	n.394T>C		non_coding_transcript_exon_variant	Exon 3 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0211

AC:

3215

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00558

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0110

Gnomad ASJ

AF:

0.0245

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0384

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0334

Gnomad OTH

AF:

0.0148

GnomAD2 exomes

AF:

0.0228

AC:

5741

AN:

251380

AF XY:

0.0230

show subpopulations

Gnomad AFR exome

AF:

0.00412

Gnomad AMR exome

AF:

0.0100

Gnomad ASJ exome

AF:

0.0243

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.0370

Gnomad NFE exome

AF:

0.0355

Gnomad OTH exome

AF:

0.0217

GnomAD4 exome

AF:

0.0298

AC:

43635

AN:

1461818

Hom.:

801

Cov.:

AF XY:

0.0292

AC XY:

21220

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.00460

AC:

154

AN:

33480

American (AMR)

AF:

0.0105

AC:

469

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0254

AC:

663

AN:

26132

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00409

AC:

353

AN:

86258

European-Finnish (FIN)

AF:

0.0389

AC:

2076

AN:

53418

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0346

AC:

38465

AN:

1111950

Other (OTH)

AF:

0.0230

AC:

1392

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

2409

4819

7228

9638

12047

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1398

2796

4194

5592

6990

<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:

0.0211

AC:

3215

AN:

152248

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1532

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.00556

AC:

231

AN:

41542

American (AMR)

AF:

0.0110

AC:

168

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0245

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00290

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0384

AC:

407

AN:

10598

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0334

AC:

2271

AN:

68018

Other (OTH)

AF:

0.0147

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

159

317

476

634

793

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0310

Hom.:

130

Bravo

AF:

0.0186

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0315

EpiControl

AF:

0.0305

ClinVar

Significance: Benign

Submissions summary: Benign:6

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

- -

Nov 07, 2016

GeneDx

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

- -

Hereditary spastic paraplegia

Benign:1

Nov 09, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ALDH18A1-related de Barsy syndrome

Benign:1

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 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

-0.78

CADD

Benign

0.33

(source)

DANN

Benign

0.70

PhyloP100

-0.46

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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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