X-38411937-G-T

Variant names:

• chrX-38411937-G-T
• rs72558470
• NM_000531.6:c.943G>T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000531.6(OTC):​c.943G>T​(p.Val315Phe) 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 (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.43

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-38411937-G-T is Pathogenic according to our data. Variant chrX-38411937-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97365.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.943G>T	p.Val315Phe	missense_variant	Exon 9 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.943G>T	p.Val315Phe	missense_variant	Exon 11 of 12		NP_001394021.1
OTC	XM_017029556.2	c.*76G>T		downstream_gene_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.943G>T	p.Val315Phe	missense_variant	Exon 9 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-254184G>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1
OTC	ENST00000643344.1	n.*693G>T		non_coding_transcript_exon_variant	Exon 10 of 11			ENSP00000496606.1
OTC	ENST00000643344.1	n.*693G>T		3_prime_UTR_variant	Exon 10 of 11			ENSP00000496606.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Sep 20, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The OTC c.943G>T (p.Val315Phe) variant involves the alteration of a conserved nucleotide. Val315 is located in the Aspartate/ornithine carbamoyltransferase, Asp/Orn-binding domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent in 87705 control chromosomes. p.Val315Gly and p.Val315Asp have been classified as pathogenic in ClinVar and HGMD, suggesting Val315 is critical for the function of OTC protein. In addition, one clinical diagnostic laboratory/reputable database has classified this variant as pathogenic. Taken together, this variant is classified as likely pathogenic until additional data becomes available (occurrences in OTCD patients and functional studies). -

not provided Pathogenic:1

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.88	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	4.5	H
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.90		Gain of helix (P = 0.132);
MVP		1.0
MPC		1.3
ClinPred		1.0	D
GERP RS		4.3
Varity_R		0.99
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs72558470; hg19: chrX-38271190;