chrX-38369849-T-C

Variant names:

• chrX-38369849-T-C
• rs72554342
• NM_000531.6:c.270T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_000531.6(OTC):​c.270T>C​(p.Ser90Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,198,207 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. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.0000028 (0 hom. 1 hem.)
• Consequence: OTC NM_000531.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.313
• Publications: 6 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-38369849-T-C is Benign according to our data. Variant chrX-38369849-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 589416.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.313 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6	c.270T>C	p.Ser90Ser	synonymous_variant	Exon 3 of 10	ENST00000039007.5	NP_000522.3
OTC	NM_001407092.1	c.270T>C	p.Ser90Ser	synonymous_variant	Exon 5 of 12		NP_001394021.1
OTC	XM_017029556.2	c.270T>C	p.Ser90Ser	synonymous_variant	Exon 3 of 9		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5	c.270T>C	p.Ser90Ser	synonymous_variant	Exon 3 of 10	1	NM_000531.6	ENSP00000039007.4
ENSG00000250349	ENST00000465127.1	c.172-296272T>C		intron_variant	Intron 3 of 8	5		ENSP00000417050.1

Frequencies

GnomAD3 genomes AF: 0.0000267 AC: 3 AN: 112181 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

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: 0.00000546 AC: 1 AN: 183148 AF XY: 0.0000148

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: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000276 AC: 3 AN: 1086026 Hom.: 0 Cov.: 25 AF XY: 0.00000284 AC XY: 1 AN XY: 352238

African (AFR) AF: 0.00 AC: 0 AN: 26206

American (AMR) AF: 0.00 AC: 0 AN: 35173

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19277

East Asian (EAS) AF: 0.00 AC: 0 AN: 30121

South Asian (SAS) AF: 0.00 AC: 0 AN: 53747

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40468

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4099

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 831238

Other (OTH) AF: 0.0000656 AC: 3 AN: 45697

GnomAD4 genome AF: 0.0000267 AC: 3 AN: 112181 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34325

African (AFR) AF: 0.0000324 AC: 1 AN: 30875

American (AMR) AF: 0.000190 AC: 2 AN: 10548

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2655

East Asian (EAS) AF: 0.00 AC: 0 AN: 3618

South Asian (SAS) AF: 0.00 AC: 0 AN: 2712

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53296

Other (OTH) AF: 0.00 AC: 0 AN: 1507

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ornithine carbamoyltransferase deficiency Benign:2

Sep 29, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 31, 2023

All of Us Research Program, National Institutes of Health

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Oct 03, 2016

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	8.2
DANN	Benign	0.76
PhyloP100		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs72554342; hg19: chrX-38229102;