chrX-38352698-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_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

Scores

6
5
3

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 4.04
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1
Start lost variant, no new inframe start found.
PS1
Another start lost variant in NM_000531.6 (OTC) was described as [Pathogenic] in ClinVar as 97131
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/exons MANE UniProt
OTCNM_000531.6 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/10 ENST00000039007.5
OTCNM_001407092.1 linkuse as main transcriptc.2T>C p.Met1? start_lost 3/12
OTCXM_017029556.2 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OTCENST00000039007.5 linkuse as main transcriptc.2T>C p.Met1? start_lost 1/101 NM_000531.6 P1
OTCENST00000488812.1 linkuse as main transcriptn.94T>C non_coding_transcript_exon_variant 1/65
OTCENST00000643344.1 linkuse as main transcriptc.2T>C p.Met1? start_lost, NMD_transcript_variant 1/11

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
27
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 03, 2021For 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). This sequence change affects the initiator methionine of the OTC mRNA. The next in-frame methionine is located at codon p.Met21. -
not provided Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyGenMed Metabolism Lab-- -

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
MutationTaster
Benign
1.0
D
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
Varity_R
0.76
gMVP
0.91

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs72552295; hg19: chrX-38211951; API