10-95606806-A-G

Position:

• chr10-95606806-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PM5 PP3 PP5_Moderate

The NM_002860.4(ALDH18A1):​c.2344T>C​(p.Tyr782His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y782S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH18A1 NM_002860.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.81

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr10-95606805-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 382498.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.835
• PP5: Variant 10-95606806-A-G is Pathogenic according to our data. Variant chr10-95606806-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2920660.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH18A1	NM_002860.4	c.2344T>C	p.Tyr782His	missense_variant	18/18	ENST00000371224.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH18A1	ENST00000371224.7	c.2344T>C	p.Tyr782His	missense_variant	18/18	1	NM_002860.4	P3
ALDH18A1	ENST00000371221.3	c.2338T>C	p.Tyr780His	missense_variant	18/18	1		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

ALDH18A1-related de Barsy syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Pediatric/Medical Genetics, Ministry of Health, Qatif Central Hospital

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Pathogenic	3.3	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Pathogenic	0.87
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.030	D;D
Polyphen		0.95	P;D
Vest4		0.63
MutPred		0.79		Gain of disorder (P = 0.0089);.;
MVP		0.78
MPC		0.80
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.69
gMVP		0.82

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-97366563;