X-38352698-T-C

Variant names:

• chrX-38352698-T-C
• rs72552295
• NM_000531.6:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_000531.6(OTC):​c.2T>C​(p.Met1?) variant causes a start lost change. 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC NM_000531.6 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 4.04
• Publications: 4 publications found

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]

OTC Gene-Disease associations (from GenCC):

• ornithine carbamoyltransferase deficiency

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P, Laboratory for Molecular Medicine, Orphanet

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 8 pathogenic variants. Next in-frame start position is after 21 codons. Genomic position: 38352757. Lost 0.057 part of the original CDS.
• PS1: Another start lost variant in NM_000531.6 (OTC) was described as [Pathogenic] in ClinVar as 97189
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-38352698-T-C is Pathogenic according to our data. Variant chrX-38352698-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 97164.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.2T>C	p.Met1?	start_lost	Exon 1 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.2T>C	p.Met1?	start_lost	Exon 3 of 12		NP_001394021.1
OTC	XM_017029556.2	c.2T>C	p.Met1?	start_lost	Exon 1 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-313423T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1

Dec 03, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects the initiator methionine of the OTC mRNA. The next in-frame methionine is located at codon p.Met21. For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 97164). Disruption of the initiator codon has been observed in individual(s) with ornithine transcarbamylase deficiency (PMID: 11793483, 16786505, 33272297). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). -

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
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.67
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
PhyloP100		4.0
PROVEAN	Benign	-0.94	N
REVEL	Pathogenic	0.72
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.012	D
Polyphen		0.90	P
Vest4		0.97
MutPred		0.97		Gain of catalytic residue at M1 (P = 0.0066);
MVP		1.0
ClinPred		0.98	D
GERP RS		5.9
PromoterAI		0.048	Neutral
Varity_R		0.76
gMVP		0.91
Mutation Taster		=8/192	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs72552295; hg19: chrX-38211951;