10-95627491-A-G

Position:

chr10-95627491-A-G

Variant summary

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

The NM_002860.4(ALDH18A1):c.1029T>C(p.Ile343=) 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

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 -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 id is 258823.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-95627491-A-G is described in Lovd as [Benign]. Variant chr10-95627491-A-G is described in Lovd as [Likely_benign].

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

BS2

High Homozygotes in GnomAd4 at 60 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH18A1	NM_002860.4 linkuse as main transcript	c.1029T>C	p.Ile343=	synonymous_variant	9/18	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.1029T>C	p.Ile343=	synonymous_variant	9/18	1	NM_002860.4	ENSP00000360268	P3	P54886-1
ALDH18A1	ENST00000371221.3 linkuse as main transcript	c.1023T>C	p.Ile341=	synonymous_variant	9/18	1		ENSP00000360265	A1	P54886-2
ALDH18A1	ENST00000489386.1 linkuse as main transcript	n.394T>C		non_coding_transcript_exon_variant	3/5	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

GnomAD3 exomes

AF:

0.0228

AC:

5741

AN:

251380

Hom.:

106

AF XY:

0.0230

AC XY:

3127

AN XY:

135858

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 SAS exome

AF:

0.00385

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

Gnomad4 AFR exome

AF:

0.00460

Gnomad4 AMR exome

AF:

0.0105

Gnomad4 ASJ exome

AF:

0.0254

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00409

Gnomad4 FIN exome

AF:

0.0389

Gnomad4 NFE exome

AF:

0.0346

Gnomad4 OTH exome

AF:

0.0230

GnomAD4 genome

AF:

0.0211

AC:

3215

AN:

152248

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1532

AN XY:

74440

show subpopulations

Gnomad4 AFR

AF:

0.00556

Gnomad4 AMR

AF:

0.0110

Gnomad4 ASJ

AF:

0.0245

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0384

Gnomad4 NFE

AF:

0.0334

Gnomad4 OTH

AF:

0.0147

Alfa

AF:

0.0273

Hom.:

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

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 07, 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

Feb 01, 2024

- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Nov 09, 2021

- -

ALDH18A1-related de Barsy syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 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

-0.78

CADD

Benign

0.33

DANN

Benign

0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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