rs68031618

Variant names:

• chrX-38352773-G-A
• rs68031618
• NM_000531.6:c.77G>A

Your query was ambiguous. Multiple possible variants found:

• chrX-38352773-G-A
• chrX-38352773-G-C
• chrX-38352773-G-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM5 PP2 PP5_Very_Strong

The NM_000531.6(OTC):​c.77G>A​(p.Arg26Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R26P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OTC NM_000531.6 missense, splice_region
• Scores: Splicing: ADA: 0.9174
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 1.65
• Publications: 11 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: Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ENSG00000250349 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38352773-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 97319.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.
• PP5: Variant X-38352773-G-A is Pathogenic according to our data. Variant chrX-38352773-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 10993.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000531.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_000531.6	MANE Select	c.77G>A	p.Arg26Gln	missense splice_region	Exon 1 of 10	NP_000522.3
	OTC	NM_001407092.1		c.77G>A	p.Arg26Gln	missense splice_region	Exon 3 of 12	NP_001394021.1	P00480

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	ENST00000039007.5	TSL:1 MANE Select	c.77G>A	p.Arg26Gln	missense splice_region	Exon 1 of 10	ENSP00000039007.4	P00480
	ENSG00000250349	ENST00000465127.1	TSL:5	c.172-313348G>A		intron	N/A	ENSP00000417050.1	B4E171
	OTC	ENST00000713758.1		c.77G>A	p.Arg26Gln	missense splice_region	Exon 3 of 12	ENSP00000519059.1	P00480

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 111984 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00 AC: 0 AN: 182778 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1066604 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 334546

African (AFR) AF: 0.00 AC: 0 AN: 25841

American (AMR) AF: 0.00 AC: 0 AN: 35169

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19176

East Asian (EAS) AF: 0.00 AC: 0 AN: 30080

South Asian (SAS) AF: 0.00 AC: 0 AN: 53390

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40453

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4057

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 813406

Other (OTH) AF: 0.00 AC: 0 AN: 45032

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 112038 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34240

African (AFR) AF: 0.00 AC: 0 AN: 30824

American (AMR) AF: 0.00 AC: 0 AN: 10550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3589

South Asian (SAS) AF: 0.00 AC: 0 AN: 2700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6100

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53208

Other (OTH) AF: 0.00 AC: 0 AN: 1518

Alfa AF: 0.0000258 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
6	-	-	Ornithine carbamoyltransferase deficiency (6)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.64	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Benign	1.1	L
PhyloP100		1.6
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.34	N
REVEL	Uncertain	0.56
Sift	Benign	0.32	T
Sift4G	Benign	0.58	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.87		Loss of MoRF binding (P = 0.0199)
MVP		0.97
MPC		0.43
ClinPred		0.19	T
GERP RS		3.8
PromoterAI		-0.16	Neutral
Varity_R		0.10
gMVP		0.68
Mutation Taster		=39/61	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.92
dbscSNV1_RF	Pathogenic	0.85
SpliceAI score (max)		0.020		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: rs68031618; hg19: chrX-38212026; COSMIC: COSV50000101;