rs1804934

Positions:

chr10-95611389-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_002860.4(ALDH18A1):c.1977C>T(p.Ser659Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0252 in 1,614,154 control chromosomes in the GnomAD database, including 550 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 76 hom., cov: 33)

Exomes 𝑓: 0.025 ( 474 hom. )

Consequence

ALDH18A1
NM_002860.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.90

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:

ALDH18A1 (HGNC:):

ALDH18A1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 10-95611389-G-A is Benign according to our data. Variant chr10-95611389-G-A is described in ClinVar as [Benign]. Clinvar id is 301761.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95611389-G-A is described in Lovd as [Benign]. Variant chr10-95611389-G-A is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-2.9 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0289 (4398/152266) while in subpopulation AFR AF= 0.0402 (1670/41540). AF 95% confidence interval is 0.0386. There are 76 homozygotes in gnomad4. There are 2090 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 76 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH18A1	NM_002860.4 linkuse as main transcript	c.1977C>T	p.Ser659Ser	synonymous_variant	16/18	ENST00000371224.7	NP_002851.2	P54886-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ALDH18A1	ENST00000371224.7 linkuse as main transcript	c.1977C>T	p.Ser659Ser	synonymous_variant	16/18	1	NM_002860.4	ENSP00000360268.2	P54886-1
ALDH18A1	ENST00000371221.3 linkuse as main transcript	c.1971C>T	p.Ser657Ser	synonymous_variant	16/18	1		ENSP00000360265.3	P54886-2
ALDH18A1	ENST00000485428.1 linkuse as main transcript	n.593C>T		non_coding_transcript_exon_variant	4/4	2

Frequencies

GnomAD3 genomes

AF:

0.0289

AC:

4394

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0401

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0319

Gnomad ASJ

AF:

0.0450

Gnomad EAS

AF:

0.0100

Gnomad SAS

AF:

0.0174

Gnomad FIN

AF:

0.0183

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0246

Gnomad OTH

AF:

0.0373

GnomAD3 exomes

AF:

0.0231

AC:

5808

AN:

251446

Hom.:

101

AF XY:

0.0226

AC XY:

3071

AN XY:

135896

show subpopulations

Gnomad AFR exome

AF:

0.0404

Gnomad AMR exome

AF:

0.0203

Gnomad ASJ exome

AF:

0.0443

Gnomad EAS exome

AF:

0.0117

Gnomad SAS exome

AF:

0.0163

Gnomad FIN exome

AF:

0.0167

Gnomad NFE exome

AF:

0.0242

Gnomad OTH exome

AF:

0.0285

GnomAD4 exome

AF:

0.0248

AC:

36307

AN:

1461888

Hom.:

474

Cov.:

AF XY:

0.0243

AC XY:

17702

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.0428

Gnomad4 AMR exome

AF:

0.0213

Gnomad4 ASJ exome

AF:

0.0456

Gnomad4 EAS exome

AF:

0.0139

Gnomad4 SAS exome

AF:

0.0164

Gnomad4 FIN exome

AF:

0.0177

Gnomad4 NFE exome

AF:

0.0251

Gnomad4 OTH exome

AF:

0.0295

GnomAD4 genome

AF:

0.0289

AC:

4398

AN:

152266

Hom.:

Cov.:

AF XY:

0.0281

AC XY:

2090

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0402

Gnomad4 AMR

AF:

0.0318

Gnomad4 ASJ

AF:

0.0450

Gnomad4 EAS

AF:

0.0100

Gnomad4 SAS

AF:

0.0172

Gnomad4 FIN

AF:

0.0183

Gnomad4 NFE

AF:

0.0246

Gnomad4 OTH

AF:

0.0369

Alfa

AF:

0.0274

Hom.:

Bravo

AF:

0.0311

Asia WGS

AF:

0.0190

AC:

AN:

3478

EpiCase

AF:

0.0291

EpiControl

AF:

0.0267

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 05, 2016

- -

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

Jan 31, 2024

- -

ALDH18A1-related de Barsy syndrome

Benign:1

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. -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 30, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.44

DANN

Benign

0.60

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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