rs72558429

chrX-38408776-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_000531.6(OTC):c.698C>T(p.Ala233Val) variant causes a missense change. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A233A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.41

Genes affected

OTC (HGNC:8512): (ornithine transcarbamylase) This nuclear gene encodes a mitochondrial matrix enzyme. The encoded protein is involved in the urea cycle which functions to detoxify ammonia into urea for excretion. Mutations in this enzyme lead to ornithine transcarbamylase deficiency, which causes hyperammonemia. [provided by RefSeq, May 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000531.6
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant X-38408776-C-T is Pathogenic according to our data. Variant chrX-38408776-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 97293.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.698C>T	p.Ala233Val	missense_variant	7/10	ENST00000039007.5
OTC	NM_001407092.1	c.698C>T	p.Ala233Val	missense_variant	9/12
OTC	XM_017029556.2	c.698C>T	p.Ala233Val	missense_variant	7/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.698C>T	p.Ala233Val	missense_variant	7/10	1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*448C>T		3_prime_UTR_variant, NMD_transcript_variant	8/11

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1091767 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 357491

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.83	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.9	N
REVEL	Pathogenic	0.86
Sift	Benign	0.11	T
Sift4G	Benign	0.20	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.88		Loss of ubiquitination at K238 (P = 0.0422);
MVP		0.99
MPC		1.1
ClinPred		0.94	D
GERP RS		5.9
Varity_R		0.65
gMVP		0.95

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.39		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.39		Position offset: 19

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

Publications

LitVar

Other links and lift over

dbSNP: rs72558429; hg19: chrX-38268029;