rs368147360

Variant names:

• chr10-95628433-C-T
• rs368147360
• NM_002860.4:c.868G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_002860.4(ALDH18A1):​c.868G>A​(p.Gly290Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000508 in 1,613,926 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: ALDH18A1 NM_002860.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.46
• 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):

• autosomal recessive complex spastic paraplegia type 9B

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Orphanet
• cutis laxa, autosomal dominant 3

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

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

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

  Inheritance: SD, AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• 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: Uncertain_significance. The variant received 0 ACMG points.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH18A1	NM_002860.4	MANE Select	c.868G>A	p.Gly290Arg	missense	Exon 8 of 18	NP_002851.2
	ALDH18A1	NM_001323413.2		c.868G>A	p.Gly290Arg	missense	Exon 8 of 18	NP_001310342.1	P54886-1
	ALDH18A1	NM_001323414.2		c.868G>A	p.Gly290Arg	missense	Exon 8 of 18	NP_001310343.1	P54886-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH18A1	ENST00000371224.7	TSL:1 MANE Select	c.868G>A	p.Gly290Arg	missense	Exon 8 of 18	ENSP00000360268.2	P54886-1
	ALDH18A1	ENST00000371221.3	TSL:1	c.862G>A	p.Gly288Arg	missense	Exon 8 of 18	ENSP00000360265.3	P54886-2
	ALDH18A1	ENST00000879381.1		c.868G>A	p.Gly290Arg	missense	Exon 8 of 18	ENSP00000549440.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152136 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000637 AC: 16 AN: 251312 AF XY: 0.0000294

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000486 AC: 71 AN: 1461790 Hom.: 0 Cov.: 31 AF XY: 0.0000495 AC XY: 36 AN XY: 727194

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.000277 AC: 11 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53388

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000441 AC: 49 AN: 1111948

Other (OTH) AF: 0.0000497 AC: 3 AN: 60394

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74312

African (AFR) AF: 0.0000966 AC: 4 AN: 41428

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Cutis laxa, autosomal dominant 3 (1)
-	1	-	de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	-0.030
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Benign	0.050	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Benign	-0.37	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.5
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.33
Sift	Benign	0.35	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.78
MutPred		0.42		Gain of solvent accessibility (P = 0.0306)
MVP		0.54
MPC		2.0
ClinPred		0.26	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.88
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs368147360; hg19: chr10-97388190; COSMIC: COSV64662043;