dbSNP rs67870244: OTC:p.His302Gln (chrX-38411900-C-G) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PS1_ModeratePM1PM2PM5PP3PP5

The NM_000531.6(OTC):c.906C>G(p.His302Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,099 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). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H302L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

OTC
NM_000531.6 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.971

Variant links:

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 links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PS1

Transcript NM_000531.6 (OTC) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

PM1

In a strand (size 3) in uniprot entity OTC_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant X-38411900-C-G is Pathogenic according to our data. Variant chrX-38411900-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 97354.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 link	c.906C>G	p.His302Gln	missense_variant	Exon 9 of 10	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 link	c.906C>G	p.His302Gln	missense_variant	Exon 11 of 12		NP_001394021.1
OTC	XM_017029556.2 link	c.*39C>G		downstream_gene_variant			XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OTC	ENST00000039007.5 link	c.906C>G	p.His302Gln	missense_variant	Exon 9 of 10	1	NM_000531.6	ENSP00000039007.4	P00480
ENSG00000250349	ENST00000465127.1 link	c.172-254221C>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1	B4E171
OTC	ENST00000643344.1 link	n.*656C>G		non_coding_transcript_exon_variant	Exon 10 of 11			ENSP00000496606.1	A0A2R8Y829
OTC	ENST00000643344.1 link	n.*656C>G		3_prime_UTR_variant	Exon 10 of 11			ENSP00000496606.1	A0A2R8Y829

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097099

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

362493

show subpopulations

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:

0.00000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

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

1.0

BayesDel_addAF

Pathogenic

0.68

BayesDel_noAF

Pathogenic

0.74

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.99

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

1.0

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

1.0

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

4.6

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.99

Loss of catalytic residue at C303 (P = 0.062);

MVP

1.0

MPC

1.2

ClinPred

1.0

GERP RS

4.1

Varity_R

1.0

gMVP

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.65

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.65

Position offset: 1

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over