X-38408795-G-C

Variant names:

• chrX-38408795-G-C
• rs66851495
• NM_000531.6:c.717G>C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000531.6(OTC):​c.717G>C​(p.Glu239Asp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.75

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]

ENSG00000250349 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-38408795-G-C is Pathogenic according to our data. Variant chrX-38408795-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.717G>C	p.Glu239Asp	missense_variant, splice_region_variant	Exon 7 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.717G>C	p.Glu239Asp	missense_variant, splice_region_variant	Exon 9 of 12		NP_001394021.1
OTC	XM_017029556.2	c.717G>C	p.Glu239Asp	missense_variant, splice_region_variant	Exon 7 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.717G>C	p.Glu239Asp	missense_variant, splice_region_variant	Exon 7 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-257326G>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000643344.1	n.*467G>C		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 11			ENSP00000496606.1
OTC	ENST00000643344.1	n.*467G>C		3_prime_UTR_variant	Exon 8 of 11			ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Feb 06, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified in the heterozygous state in a female and reported as a mutation associated with OTC deficiency in published literature (PMID: 16786505); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 16786505, 26059767) -

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GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Ornithine carbamoyltransferase deficiency Pathogenic:1

May 28, 2019

Mendelics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Benign	1.8	L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.7	N
REVEL	Pathogenic	0.67
Sift	Benign	0.084	T
Sift4G	Benign	0.14	T
Polyphen		0.18	B
Vest4		0.43
MutPred		0.84		Loss of phosphorylation at Y236 (P = 0.083);
MVP		1.0
MPC		0.52
ClinPred		0.57	D
GERP RS		5.7
Varity_R		0.58
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.86		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.86		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: rs66851495; hg19: chrX-38268048;