chr10-95644607-C-A

Variant names:

• chr10-95644607-C-A
• rs10882645
• NM_002860.4:c.89-1401G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002860.4(ALDH18A1):​c.89-1401G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 152,058 control chromosomes in the GnomAD database, including 10,013 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (10013 hom., cov: 32)
• Consequence: ALDH18A1 NM_002860.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.477
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• cutis laxa, autosomal dominant 3

  Inheritance: AD, SD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• ALDH18A1-related de Barsy syndrome

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive complex spastic paraplegia type 9B

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• P5CS deficiency

  Inheritance: SD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
• hereditary spastic paraplegia 9A

  Inheritance: AD, SD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• autosomal dominant complex spastic paraplegia type 9B

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• autosomal dominant cutis laxa

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.678 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH18A1	NM_002860.4	c.89-1401G>T		intron_variant	Intron 2 of 17	ENST00000371224.7	NP_002851.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.89-1401G>T		intron_variant	Intron 2 of 17	1	NM_002860.4	ENSP00000360268.2
ALDH18A1	ENST00000371221.3	c.89-1401G>T		intron_variant	Intron 2 of 17	1		ENSP00000360265.3
ALDH18A1	ENST00000483788.1	n.281-1401G>T		intron_variant	Intron 2 of 4	3

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53337 AN: 151940 Hom.: 10001 Cov.: 32

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.341

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.409

Gnomad EAS AF: 0.697

Gnomad SAS AF: 0.376

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.315

Gnomad OTH AF: 0.362

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.351 AC: 53401 AN: 152058 Hom.: 10013 Cov.: 32 AF XY: 0.350 AC XY: 26008 AN XY: 74340

African (AFR) AF: 0.407 AC: 16880 AN: 41448

American (AMR) AF: 0.266 AC: 4068 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.409 AC: 1417 AN: 3466

East Asian (EAS) AF: 0.697 AC: 3603 AN: 5172

South Asian (SAS) AF: 0.379 AC: 1824 AN: 4818

European-Finnish (FIN) AF: 0.284 AC: 3001 AN: 10576

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.315 AC: 21405 AN: 67968

Other (OTH) AF: 0.366 AC: 772 AN: 2112

Alfa AF: 0.194 Hom.: 375

Bravo AF: 0.353

Asia WGS AF: 0.531 AC: 1842 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.66
DANN	Benign	0.68
PhyloP100		-0.48
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10882645; hg19: chr10-97404364;