rs72558451

Variant names:

• chrX-38408966-C-A
• rs72558451
• NM_000531.6:c.808C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-38408966-C-A
• chrX-38408966-C-G
• chrX-38408966-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP2

The NM_000531.6(OTC):​c.808C>A​(p.Gln270Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q270P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.000016 (0 hom. 4 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.48
• Publications: 0 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38408967-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 97336.Status of the report is no_assertion_criteria_provided, 0 stars.
• 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.808C>A	p.Gln270Lys	missense_variant	Exon 8 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.808C>A	p.Gln270Lys	missense_variant	Exon 10 of 12		NP_001394021.1
OTC	XM_017029556.2	c.808C>A	p.Gln270Lys	missense_variant	Exon 8 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.808C>A	p.Gln270Lys	missense_variant	Exon 8 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-257155C>A		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000164 AC: 15 AN: 915982 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 4 AN XY: 295214

⚠️ 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: 21376

American (AMR) AF: 0.00 AC: 0 AN: 31737

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14973

East Asian (EAS) AF: 0.00 AC: 0 AN: 22397

South Asian (SAS) AF: 0.00 AC: 0 AN: 51483

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29764

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3525

European-Non Finnish (NFE) AF: 0.0000213 AC: 15 AN: 704581

Other (OTH) AF: 0.00 AC: 0 AN: 36146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000153), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.96	D
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		5.5
PrimateAI	Uncertain	0.54	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.024	D
Polyphen		0.15	B
Vest4		0.48
MutPred		0.58		Gain of methylation at Q270 (P = 0.0124);
MVP		0.98
MPC		0.55
ClinPred		0.98	D
GERP RS		5.6
Varity_R		0.90
gMVP		0.95
Mutation Taster		=92/8	polymorphism

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: rs72558451; hg19: chrX-38268219;