chrX-38408752-C-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PS1_ModeratePM2PM5PP3_StrongPP5

The NM_000531.6(OTC):​c.674C>G​(p.Pro225Arg) variant causes a missense 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 (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P225T) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

OTC
NM_000531.6 missense

Scores

11
4
2

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 5.28
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 11 ACMG points.

PS1
Transcript NM_000531.6 (OTC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant X-38408752-C-G is Pathogenic according to our data. Variant chrX-38408752-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 97291.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
OTCNM_000531.6 linkuse as main transcriptc.674C>G p.Pro225Arg missense_variant 7/10 ENST00000039007.5 NP_000522.3
OTCNM_001407092.1 linkuse as main transcriptc.674C>G p.Pro225Arg missense_variant 9/12 NP_001394021.1
OTCXM_017029556.2 linkuse as main transcriptc.674C>G p.Pro225Arg missense_variant 7/9 XP_016885045.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
OTCENST00000039007.5 linkuse as main transcriptc.674C>G p.Pro225Arg missense_variant 7/101 NM_000531.6 ENSP00000039007 P1
OTCENST00000643344.1 linkuse as main transcriptc.*424C>G 3_prime_UTR_variant, NMD_transcript_variant 8/11 ENSP00000496606

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyGenMed Metabolism Lab-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.94
BayesDel_addAF
Pathogenic
0.65
D
BayesDel_noAF
Pathogenic
0.70
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.97
D
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.97
D
M_CAP
Pathogenic
0.94
D
MetaRNN
Pathogenic
0.99
D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.8
H
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-6.2
D
REVEL
Pathogenic
0.96
Sift
Benign
0.36
T
Sift4G
Uncertain
0.045
D
Polyphen
1.0
D
Vest4
0.98
MutPred
0.93
Loss of methylation at K221 (P = 0.0708);
MVP
0.99
MPC
1.2
ClinPred
0.99
D
GERP RS
5.9
Varity_R
0.96
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.12
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: rs67120076; hg19: chrX-38268005; API