rs72556251

Positions:

• chrX-38401276-G-GTAT

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP3 PP5

The NM_000531.6(OTC):​c.390_392dup​(p.Leu131_Ser131insLeu) variant causes a inframe insertion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. V130V) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 24)
• Consequence: OTC NM_000531.6 inframe_insertion, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.63

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000531.6
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000531.6. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-38401276-G-GTAT is Pathogenic according to our data. Variant chrX-38401276-G-GTAT is described in ClinVar as [Pathogenic]. Clinvar id is 97185.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OTC	NM_000531.6	c.390_392dup	p.Leu131_Ser131insLeu	inframe_insertion, splice_region_variant	5/10	ENST00000039007.5
OTC	NM_001407092.1	c.390_392dup	p.Leu131_Ser131insLeu	inframe_insertion, splice_region_variant	7/12
OTC	XM_017029556.2	c.390_392dup	p.Leu131_Ser131insLeu	inframe_insertion, splice_region_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OTC	ENST00000039007.5	c.390_392dup	p.Leu131_Ser131insLeu	inframe_insertion, splice_region_variant	5/10	1	NM_000531.6	P1
OTC	ENST00000488812.1	n.427_429dup		splice_region_variant, non_coding_transcript_exon_variant	5/6	5
OTC	ENST00000643344.1	c.*140_*142dup		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	6/11

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 24

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

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs72556251; hg19: chrX-38260529;