Genetic Variant ENSG00000250349:c.172-313718G>A (chrX-38352403-G-A) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001407092.1(OTC):c.-79-215G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 295,497 control chromosomes in the GnomAD database, including 17 homozygotes. There are 256 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 0.0070 ( 13 hom., 210 hem., cov: 22)

Exomes 𝑓: 0.0012 ( 4 hom. 46 hem. )

Consequence

OTC
NM_001407092.1 intron

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.947

Publications

3 publications found

Variant links:

Genes affected

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

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: Orphanet, Laboratory for Molecular Medicine, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

OTC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant X-38352403-G-A is Benign according to our data. Variant chrX-38352403-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1190289.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00701 (779/111206) while in subpopulation AFR AF = 0.0236 (721/30549). AF 95% confidence interval is 0.0222. There are 13 homozygotes in GnomAd4. There are 210 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001407092.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OTC	NM_001407092.1		c.-79-215G>A		intron	N/A	NP_001394021.1	P00480
	OTC	NM_000531.6	MANE Select	c.-294G>A		upstream_gene	N/A	NP_000522.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ENSG00000250349	ENST00000465127.1	TSL:5	c.172-313718G>A	intron	N/A	ENSP00000417050.1	B4E171
OTC	ENST00000713758.1		c.-79-215G>A	intron	N/A	ENSP00000519059.1	P00480
OTC	ENST00000909233.1		c.-79-215G>A	intron	N/A	ENSP00000579292.1

Frequencies

GnomAD3 genomes

AF:

0.00697

AC:

775

AN:

111153

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0235

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00404

Gnomad ASJ

AF:

0.000379

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000169

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00879

GnomAD4 exome

AF:

0.00117

AC:

215

AN:

184291

Hom.:

AF XY:

0.000829

AC XY:

AN XY:

55461

show subpopulations

African (AFR)

AF:

0.0217

AC:

131

AN:

6034

American (AMR)

AF:

0.00273

AC:

AN:

9540

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

5172

East Asian (EAS)

AF:

0.000192

AC:

AN:

10399

South Asian (SAS)

AF:

0.000137

AC:

AN:

21933

European-Finnish (FIN)

AF:

0.000560

AC:

AN:

8936

Middle Eastern (MID)

AF:

0.00143

AC:

AN:

699

European-Non Finnish (NFE)

AF:

0.0000541

AC:

AN:

110873

Other (OTH)

AF:

0.00383

AC:

AN:

10705

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00701

AC:

779

AN:

111206

Hom.:

Cov.:

AF XY:

0.00628

AC XY:

210

AN XY:

33458

show subpopulations

African (AFR)

AF:

0.0236

AC:

721

AN:

30549

American (AMR)

AF:

0.00404

AC:

AN:

10399

Ashkenazi Jewish (ASJ)

AF:

0.000379

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3561

South Asian (SAS)

AF:

0.00

AC:

AN:

2665

European-Finnish (FIN)

AF:

0.000169

AC:

AN:

5901

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53091

Other (OTH)

AF:

0.00868

AC:

AN:

1498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00712

Hom.:

Bravo

AF:

0.00821

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

0.95

PromoterAI

-0.0068

Neutral

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over