NM_002860.4:c.1115C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002860.4(ALDH18A1):c.1115C>A(p.Ser372Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 1,613,874 control chromosomes in the GnomAD database, including 340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.015 ( 29 hom., cov: 32)

Exomes 𝑓: 0.019 ( 311 hom. )

Consequence

ALDH18A1
NM_002860.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 3.29

Publications

17 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=0.0072588027).

BP6

Variant 10-95626740-G-T is Benign according to our data. Variant chr10-95626740-G-T is described in ClinVar as Benign. ClinVar VariationId is 301770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0149 (2271/152178) while in subpopulation EAS AF = 0.0376 (194/5158). AF 95% confidence interval is 0.0333. There are 29 homozygotes in GnomAd4. There are 1098 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 29 AR,AD,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH18A1	NM_002860.4 link	c.1115C>A	p.Ser372Tyr	missense_variant	Exon 10 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.1115C>A	p.Ser372Tyr	missense_variant	Exon 10 of 18	1	NM_002860.4	ENSP00000360268.2	P54886-1
ALDH18A1	ENST00000371221.3 link	c.1109C>A	p.Ser370Tyr	missense_variant	Exon 10 of 18	1		ENSP00000360265.3	P54886-2
ALDH18A1	ENST00000489386.1 link	n.480C>A		non_coding_transcript_exon_variant	Exon 4 of 5	3

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2274

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00650

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.0373

Gnomad SAS

AF:

0.0180

Gnomad FIN

AF:

0.00387

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0190

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0174

AC:

4382

AN:

251460

AF XY:

0.0187

show subpopulations

Gnomad AFR exome

AF:

0.00547

Gnomad AMR exome

AF:

0.00885

Gnomad ASJ exome

AF:

0.0320

Gnomad EAS exome

AF:

0.0377

Gnomad FIN exome

AF:

0.00457

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0194

GnomAD4 exome

AF:

0.0191

AC:

27955

AN:

1461696

Hom.:

311

Cov.:

AF XY:

0.0195

AC XY:

14157

AN XY:

727162

show subpopulations

African (AFR)

AF:

0.00624

AC:

209

AN:

33478

American (AMR)

AF:

0.00917

AC:

410

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0286

AC:

748

AN:

26128

East Asian (EAS)

AF:

0.0361

AC:

1434

AN:

39698

South Asian (SAS)

AF:

0.0169

AC:

1454

AN:

86256

European-Finnish (FIN)

AF:

0.00468

AC:

250

AN:

53408

Middle Eastern (MID)

AF:

0.0343

AC:

198

AN:

5768

European-Non Finnish (NFE)

AF:

0.0199

AC:

22097

AN:

1111852

Other (OTH)

AF:

0.0191

AC:

1155

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1480

2959

4439

5918

7398

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.0149

AC:

2271

AN:

152178

Hom.:

Cov.:

AF XY:

0.0148

AC XY:

1098

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00648

AC:

269

AN:

41506

American (AMR)

AF:

0.0141

AC:

215

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3470

East Asian (EAS)

AF:

0.0376

AC:

194

AN:

5158

South Asian (SAS)

AF:

0.0176

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00387

AC:

AN:

10596

Middle Eastern (MID)

AF:

0.0442

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0190

AC:

1290

AN:

68016

Other (OTH)

AF:

0.0242

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

113

227

340

454

567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

102

136

170

<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:

0.0194

Hom.:

136

Bravo

AF:

0.0154

TwinsUK

AF:

0.0200

AC:

ALSPAC

AF:

0.0231

AC:

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.0193

AC:

166

ExAC

AF:

0.0172

AC:

2093

Asia WGS

AF:

0.0200

AC:

AN:

3478

EpiCase

AF:

0.0233

EpiControl

AF:

0.0241

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

ALDH18A1-related de Barsy syndrome

Benign:2

Jan 12, 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. -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign, for Cutis laxa, autosomal recessive, type IIIa, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

not specified

Benign:1

Dec 08, 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. -

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

Apr 15, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

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

- -

Cutis laxa, autosomal dominant 3;C5234852:ALDH18A1-related de Barsy syndrome;C5568978:Hereditary spastic paraplegia 9A;C5568980:Autosomal recessive complex spastic paraplegia type 9B

Benign:1

Aug 24, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.27

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.62

D;.

Eigen

Uncertain

0.24

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

D;D

MetaRNN

Benign

0.0073

T;T

MetaSVM

Benign

-0.38

MutationAssessor

Uncertain

2.1

M;.

PhyloP100

3.3

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-2.5

D;D

REVEL

Benign

0.29

Sift

Benign

0.038

D;D

Sift4G

Uncertain

0.047

D;D

Polyphen

0.021

B;B

Vest4

0.14

MPC

0.37

ClinPred

0.034

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.38

gMVP

0.53

Mutation Taster

=91/9

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

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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