rs1231068982

Variant names:

• chr10-95613990-T-C
• rs1231068982
• NM_002860.4:c.1777A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002860.4(ALDH18A1):​c.1777A>G​(p.Ser593Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S593T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH18A1 NM_002860.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.61
• 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):

• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1777A>G	p.Ser593Gly	missense	Exon 14 of 18	NP_002851.2
	ALDH18A1	NM_001323413.2		c.1777A>G	p.Ser593Gly	missense	Exon 14 of 18	NP_001310342.1	P54886-1
	ALDH18A1	NM_001323414.2		c.1777A>G	p.Ser593Gly	missense	Exon 14 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.1777A>G	p.Ser593Gly	missense	Exon 14 of 18	ENSP00000360268.2	P54886-1
	ALDH18A1	ENST00000371221.3	TSL:1	c.1771A>G	p.Ser591Gly	missense	Exon 14 of 18	ENSP00000360265.3	P54886-2
	ALDH18A1	ENST00000879381.1		c.1777A>G	p.Ser593Gly	missense	Exon 14 of 18	ENSP00000549440.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251172 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	de Barsy syndrome;C1832669:Autosomal dominant spastic paraplegia type 9;C4225268:Cutis laxa, autosomal dominant 3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Benign	0.058
Eigen_PC	Benign	0.16
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.015	D
Polyphen		0.21	B
Vest4		0.57
MutPred		0.56		Loss of stability (P = 0.0368)
MVP		0.67
MPC		0.29
ClinPred		0.55	D
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.62
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs1231068982; hg19: chr10-97373747;