rs11188411

Positions:

• chr10-95637587-T-C
• chr10-95637587-T-G

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.304-151A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.294 in 877,912 control chromosomes in the GnomAD database, including 43,227 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.28 (6787 hom., cov: 32)
  • Exomes 𝑓: 0.30 (36440 hom.)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.12

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=-0.91).
• BP6: Variant 10-95637587-T-C is Benign according to our data. Variant chr10-95637587-T-C is described in ClinVar as [Benign]. Clinvar id is 1297419.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH18A1	NM_002860.4	c.304-151A>G		intron_variant		ENST00000371224.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.304-151A>G		intron_variant		1	NM_002860.4	P3
ALDH18A1	ENST00000371221.3	c.304-151A>G		intron_variant		1		A1
ALDH18A1	ENST00000483788.1	n.496-151A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.277 AC: 42087 AN: 152010 Hom.: 6795 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.0439

Gnomad SAS AF: 0.218

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.225

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.260

GnomAD4 exome AF: 0.298 AC: 215932 AN: 725784 Hom.: 36440 AF XY: 0.295 AC XY: 110081 AN XY: 373418

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.433

Gnomad4 ASJ exome AF: 0.214

Gnomad4 EAS exome AF: 0.0491

Gnomad4 SAS exome AF: 0.220

Gnomad4 FIN exome AF: 0.313

Gnomad4 NFE exome AF: 0.325

Gnomad4 OTH exome AF: 0.287

GnomAD4 genome AF: 0.277 AC: 42069 AN: 152128 Hom.: 6787 Cov.: 32 AF XY: 0.275 AC XY: 20446 AN XY: 74368

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.395

Gnomad4 ASJ AF: 0.218

Gnomad4 EAS AF: 0.0435

Gnomad4 SAS AF: 0.217

Gnomad4 FIN AF: 0.316

Gnomad4 NFE AF: 0.353

Gnomad4 OTH AF: 0.256

Alfa AF: 0.254 Hom.: 1313

Bravo AF: 0.280

Asia WGS AF: 0.128 AC: 447 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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.31
DANN	Benign	0.70

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: rs11188411; hg19: chr10-97397344;