chrX-38408794-A-G

Position:

• chrX-38408794-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000039007.5(OTC):​c.716A>G​(p.Glu239Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E239V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OTC ENST00000039007.5 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 6.35

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]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 3 uncertain in ENST00000039007.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-38408795-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 97302.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-38408794-A-G is Pathogenic according to our data. Variant chrX-38408794-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 97295.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OTC	NM_000531.6	c.716A>G	p.Glu239Gly	missense_variant, splice_region_variant	7/10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.716A>G	p.Glu239Gly	missense_variant, splice_region_variant	9/12		NP_001394021.1
OTC	XM_017029556.2	c.716A>G	p.Glu239Gly	missense_variant, splice_region_variant	7/9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.716A>G	p.Glu239Gly	missense_variant, splice_region_variant	7/10	1	NM_000531.6	ENSP00000039007	P1
OTC	ENST00000643344.1	c.*466A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	8/11			ENSP00000496606

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

GenMed Metabolism Lab

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.85
Sift	Benign	0.10	T
Sift4G	Benign	0.10	T
Polyphen		0.85	P
Vest4		0.85
MutPred		0.86		Gain of ubiquitination at K243 (P = 0.0695);
MVP		0.99
MPC		1.1
ClinPred		0.97	D
GERP RS		5.7
Varity_R		0.52
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
SpliceAI score (max)		0.79		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.79		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs67283833; hg19: chrX-38268047;