rs3765571

Positions:

chr10-95626740-G-T

Variant summary

Our verdict is Benign. Variant got -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

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=0.0072588027).

BP6

Variant 10-95626740-G-T is Benign according to our data. Variant chr10-95626740-G-T is described in ClinVar as [Benign]. Clinvar id is 301770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95626740-G-T is described in Lovd as [Likely_benign].

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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 29 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH18A1	NM_002860.4 linkuse as main transcript	c.1115C>A	p.Ser372Tyr	missense_variant	10/18	ENST00000371224.7	NP_002851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH18A1	ENST00000371224.7 linkuse as main transcript	c.1115C>A	p.Ser372Tyr	missense_variant	10/18	1	NM_002860.4	ENSP00000360268	P3	P54886-1
ALDH18A1	ENST00000371221.3 linkuse as main transcript	c.1109C>A	p.Ser370Tyr	missense_variant	10/18	1		ENSP00000360265	A1	P54886-2
ALDH18A1	ENST00000489386.1 linkuse as main transcript	n.480C>A		non_coding_transcript_exon_variant	4/5	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

GnomAD3 exomes

AF:

0.0174

AC:

4382

AN:

251460

Hom.:

AF XY:

0.0187

AC XY:

2536

AN XY:

135908

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 SAS exome

AF:

0.0161

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

Gnomad4 AFR exome

AF:

0.00624

Gnomad4 AMR exome

AF:

0.00917

Gnomad4 ASJ exome

AF:

0.0286

Gnomad4 EAS exome

AF:

0.0361

Gnomad4 SAS exome

AF:

0.0169

Gnomad4 FIN exome

AF:

0.00468

Gnomad4 NFE exome

AF:

0.0199

Gnomad4 OTH exome

AF:

0.0191

GnomAD4 genome

AF:

0.0149

AC:

2271

AN:

152178

Hom.:

Cov.:

AF XY:

0.0148

AC XY:

1098

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00648

Gnomad4 AMR

AF:

0.0141

Gnomad4 ASJ

AF:

0.0314

Gnomad4 EAS

AF:

0.0376

Gnomad4 SAS

AF:

0.0176

Gnomad4 FIN

AF:

0.00387

Gnomad4 NFE

AF:

0.0190

Gnomad4 OTH

AF:

0.0242

Alfa

AF:

0.0203

Hom.:

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

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 08, 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. -

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

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Apr 15, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

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

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 24, 2021

- -

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

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;.

MutationTaster

Benign

0.91

D;D

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

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