X-38367288-C-T

Variant names:

• chrX-38367288-C-T
• rs72554303
• NM_000531.6:c.78-3C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000531.6(OTC):​c.78-3C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,088,530 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: OTC NM_000531.6 splice_region, intron
• Scores: Splicing: ADA: 0.0001392
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.611
• Publications: 1 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_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.78-3C>T		splice_region_variant, intron_variant	Intron 1 of 9	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.78-3C>T		splice_region_variant, intron_variant	Intron 3 of 11		NP_001394021.1
OTC	XM_017029556.2	c.78-3C>T		splice_region_variant, intron_variant	Intron 1 of 8		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.78-3C>T		splice_region_variant, intron_variant	Intron 1 of 9	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-298833C>T		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000552 AC: 1 AN: 181255 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: 0.0000728

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1088530 Hom.: 0 Cov.: 27 AF XY: 0.00000282 AC XY: 1 AN XY: 354494

African (AFR) AF: 0.00 AC: 0 AN: 26204

American (AMR) AF: 0.00 AC: 0 AN: 35135

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19294

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30108

South Asian (SAS) AF: 0.00 AC: 0 AN: 53871

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00000240 AC: 2 AN: 833632

Other (OTH) AF: 0.00 AC: 0 AN: 45752

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.5
DANN	Benign	0.76
PhyloP100		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00014
dbscSNV1_RF	Benign	0.096
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: rs72554303; hg19: chrX-38226541;