rs72554358

Variant names:

• chrX-38381420-A-G
• rs72554358
• NM_000531.6:c.377A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_Moderate PM2 PP3_Strong PP5

The NM_000531.6(OTC):​c.377A>G​(p.Asp126Gly) 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 the same amino acid substitution has been previously reported as Likely pathogenic in UniProt.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 6.86

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 9 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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant X-38381420-A-G is Pathogenic according to our data. Variant chrX-38381420-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 97177.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.377A>G	p.Asp126Gly	missense_variant	Exon 4 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.377A>G	p.Asp126Gly	missense_variant	Exon 6 of 12		NP_001394021.1
OTC	XM_017029556.2	c.377A>G	p.Asp126Gly	missense_variant	Exon 4 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.377A>G	p.Asp126Gly	missense_variant	Exon 4 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-284701A>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1064544 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 332866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

-

GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Ornithine carbamoyltransferase deficiency Uncertain:1

Nov 26, 2023

3billion

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is not observed in the gnomAD v2.1.1 dataset. Predicted Consequence/Location: Missense variant In silico tool predictions suggest damaging effect of the variant on gene or gene product [REVEL: 0.98 (>=0.6, sensitivity 0.68 and specificity 0.92); 3Cnet: 0.97 (>=0.6, sensitivity 0.72 and precision 0.9)]. Same nucleotide change resulting in same amino acid change has been previously reported to be associated with OTC related disorder (ClinVar ID: VCV000097177 /PMID: 8081398). A different missense change at the same codon (p.Asp126Asn) has been reported to be associated with OTC related disorder (ClinVar ID: VCV001973524). Therefore, this variant is classified as VUS according to the recommendation of ACMG/AMP guideline. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.99	D
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	1.0	D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.6	H
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MutPred		0.99		Gain of methylation at R129 (P = 0.0803);
MVP		1.0
MPC		1.1
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs72554358; hg19: chrX-38240673;