rs72554315

Variant names:

• chrX-38367356-T-C
• rs72554315
• NM_000531.6:c.143T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PP2 PP3_Strong PP5

The NM_000531.6(OTC):​c.143T>C​(p.Phe48Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000918 in 1,089,036 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. F48F) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.73
• 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 10 ACMG points.

• PM1: In a hotspot region, there are 18 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 3 benign, 11 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 266 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 1.3274 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to ornithine carbamoyltransferase deficiency.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993
• PP5: Variant X-38367356-T-C is Pathogenic according to our data. Variant chrX-38367356-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 97115.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.143T>C	p.Phe48Ser	missense_variant	Exon 2 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.143T>C	p.Phe48Ser	missense_variant	Exon 4 of 12		NP_001394021.1
OTC	XM_017029556.2	c.143T>C	p.Phe48Ser	missense_variant	Exon 2 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.143T>C	p.Phe48Ser	missense_variant	Exon 2 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-298765T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.18e-7 AC: 1 AN: 1089036 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 354692

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26222

American (AMR) AF: 0.00 AC: 0 AN: 35194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19313

East Asian (EAS) AF: 0.00 AC: 0 AN: 30166

South Asian (SAS) AF: 0.00 AC: 0 AN: 53954

European-Finnish (FIN) AF: 0.0000247 AC: 1 AN: 40511

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4108

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 833745

Other (OTH) AF: 0.00 AC: 0 AN: 45823

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

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GenMed Metabolism Lab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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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	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.6	H
PhyloP100		2.7
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.80
MutPred		0.90		Gain of disorder (P = 0.0039);
MVP		0.99
MPC		1.6
ClinPred		0.99	D
GERP RS		5.4
Varity_R		0.99
gMVP		1.0
Mutation Taster		=28/72	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: rs72554315; hg19: chrX-38226609;