rs10882644

Positions:

• chr10-95628822-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002860.4(ALDH18A1):​c.809-330G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.292 in 361,078 control chromosomes in the GnomAD database, including 17,447 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.27 (6712 hom., cov: 32)
  • Exomes 𝑓: 0.31 (10735 hom.)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.362

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 10-95628822-C-T is Benign according to our data. Variant chr10-95628822-C-T is described in ClinVar as [Benign]. Clinvar id is 683818.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH18A1	NM_002860.4	c.809-330G>A		intron_variant		ENST00000371224.7	NP_002851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.809-330G>A		intron_variant		1	NM_002860.4	ENSP00000360268	P3
ALDH18A1	ENST00000371221.3	c.803-330G>A		intron_variant		1		ENSP00000360265	A1
ALDH18A1	ENST00000489386.1	n.32G>A		non_coding_transcript_exon_variant	1/5	3

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41626 AN: 151996 Hom.: 6720 Cov.: 32

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.365

Gnomad AMR AF: 0.392

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0440

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.317

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.255

GnomAD4 exome AF: 0.305 AC: 63743 AN: 208964 Hom.: 10735 Cov.: 0 AF XY: 0.294 AC XY: 33255 AN XY: 113276

Gnomad4 AFR exome AF: 0.131

Gnomad4 AMR exome AF: 0.424

Gnomad4 ASJ exome AF: 0.227

Gnomad4 EAS exome AF: 0.0448

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.352

Gnomad4 OTH exome AF: 0.315

GnomAD4 genome AF: 0.274 AC: 41608 AN: 152114 Hom.: 6712 Cov.: 32 AF XY: 0.272 AC XY: 20224 AN XY: 74344

Gnomad4 AFR AF: 0.129

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.0435

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.317

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.252

Alfa AF: 0.307 Hom.: 965

Bravo AF: 0.276

Asia WGS AF: 0.127 AC: 445 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2018	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. -
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	-0.89
CADD	Benign	3.8
DANN	Benign	0.37

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

Other links and lift over

dbSNP: rs10882644; hg19: chr10-97388579;