rs11188394

Variant names:

• chr10-95605701-T-C
• rs11188394
• NM_002860.4:c.*1061A>G

Variant summary

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

The NM_002860.4(ALDH18A1):​c.*1061A>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.254 in 152,092 control chromosomes in the GnomAD database, including 6,359 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 0.25 (6359 hom., cov: 32)
• Consequence: ALDH18A1 NM_002860.4 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.38
• Publications: 6 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 (AMR) allele frequency at 95% confidence interval = 0.371 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002860.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH18A1	NM_002860.4	MANE Select	c.*1061A>G		downstream_gene	N/A	NP_002851.2
	ALDH18A1	NM_001323413.2		c.*1061A>G		downstream_gene	N/A	NP_001310342.1
	ALDH18A1	NM_001323414.2		c.*1061A>G		downstream_gene	N/A	NP_001310343.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH18A1	ENST00000371224.7	TSL:1 MANE Select	c.*1061A>G		downstream_gene	N/A	ENSP00000360268.2
	ALDH18A1	ENST00000371221.3	TSL:1	c.*1061A>G		downstream_gene	N/A	ENSP00000360265.3

Frequencies

GnomAD3 genomes AF: 0.255 AC: 38678 AN: 151974 Hom.: 6366 Cov.: 32

Gnomad AFR AF: 0.0651

Gnomad AMI AF: 0.364

Gnomad AMR AF: 0.379

Gnomad ASJ AF: 0.207

Gnomad EAS AF: 0.0439

Gnomad SAS AF: 0.213

Gnomad FIN AF: 0.316

Gnomad MID AF: 0.196

Gnomad NFE AF: 0.353

Gnomad OTH AF: 0.239

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

GnomAD4 genome AF: 0.254 AC: 38659 AN: 152092 Hom.: 6359 Cov.: 32 AF XY: 0.253 AC XY: 18830 AN XY: 74342

African (AFR) AF: 0.0649 AC: 2696 AN: 41536

American (AMR) AF: 0.379 AC: 5783 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.207 AC: 718 AN: 3472

East Asian (EAS) AF: 0.0435 AC: 225 AN: 5176

South Asian (SAS) AF: 0.213 AC: 1026 AN: 4826

European-Finnish (FIN) AF: 0.316 AC: 3339 AN: 10564

Middle Eastern (MID) AF: 0.187 AC: 55 AN: 294

European-Non Finnish (NFE) AF: 0.353 AC: 23991 AN: 67954

Other (OTH) AF: 0.236 AC: 495 AN: 2100

Alfa AF: 0.295 Hom.: 928

Bravo AF: 0.253

Asia WGS AF: 0.120 AC: 422 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.88
DANN	Benign	0.29
PhyloP100		-1.4

Splicing

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

Other links and lift over

dbSNP: rs11188394; hg19: chr10-97365458;