rs72558486

Positions:

• chrX-38421023-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3_Moderate PP5

The NM_000531.6(OTC):​c.1006G>T​(p.Ala336Ser) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Synonymous variant affecting the same amino acid position (i.e. A336A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: OTC NM_000531.6 missense, splice_region
• Scores: Splicing: ADA: 0.9998
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.28

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 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.
• PP5: Variant X-38421023-G-T is Pathogenic according to our data. Variant chrX-38421023-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 97094.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.1006G>T	p.Ala336Ser	missense_variant, splice_region_variant	10/10	ENST00000039007.5
OTC	NM_001407092.1	c.1006G>T	p.Ala336Ser	missense_variant, splice_region_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.1006G>T	p.Ala336Ser	missense_variant, splice_region_variant	10/10	1	NM_000531.6	P1
OTC	ENST00000643344.1	c.*756G>T		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	11/11

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 22

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	Benign	0.21
BayesDel_addAF	Pathogenic	0.65	D
BayesDel_noAF	Pathogenic	0.69
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	2.9	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.87
Sift	Benign	0.38	T
Sift4G	Benign	0.21	T
Polyphen		0.79	P
Vest4		0.60
MutPred		0.95		Gain of ubiquitination at K331 (P = 0.1117);
MVP		0.99
MPC		0.44
ClinPred		0.96	D
GERP RS		5.3
Varity_R		0.72
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.48		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs72558486; hg19: chrX-38280276;