dbSNP rs957415: OTC:c.663+50A>G (chrX-38403790-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000531.6(OTC):c.663+50A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0042 in 1,164,513 control chromosomes in the GnomAD database, including 9 homozygotes. There are 1,613 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., 97 hem., cov: 23)

Exomes 𝑓: 0.0043 ( 8 hom. 1516 hem. )

Consequence

OTC
NM_000531.6 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.209

Publications

0 publications found

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 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

OTC links:

ENSG00000250349 (HGNC:):

ENSG00000250349 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant X-38403790-A-G is Benign according to our data. Variant chrX-38403790-A-G is described in ClinVar as Benign. ClinVar VariationId is 256371.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00297 (332/111823) while in subpopulation NFE AF = 0.00485 (258/53158). AF 95% confidence interval is 0.00437. There are 1 homozygotes in GnomAd4. There are 97 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 97 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
OTC	NM_000531.6 link	c.663+50A>G	intron_variant	Intron 6 of 9	ENST00000039007.5	NP_000522.3	P00480
OTC	NM_001407092.1 link	c.663+50A>G	intron_variant	Intron 8 of 11		NP_001394021.1
OTC	XM_017029556.2 link	c.663+50A>G	intron_variant	Intron 6 of 8		XP_016885045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OTC	ENST00000039007.5 link	c.663+50A>G		intron_variant	Intron 6 of 9	1	NM_000531.6	ENSP00000039007.4		P00480
ENSG00000250349	ENST00000465127.1 link	c.172-262331A>G		intron_variant	Intron 3 of 8	5		ENSP00000417050.1		B4E171

Frequencies

GnomAD3 genomes

AF:

0.00297

AC:

332

AN:

111770

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000650

Gnomad AMI

AF:

0.00438

Gnomad AMR

AF:

0.00247

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00419

Gnomad FIN

AF:

0.000657

Gnomad MID

AF:

0.0168

Gnomad NFE

AF:

0.00485

Gnomad OTH

AF:

0.00403

GnomAD2 exomes

AF:

0.00275

AC:

498

AN:

180767

AF XY:

0.00326

show subpopulations

Gnomad AFR exome

AF:

0.000613

Gnomad AMR exome

AF:

0.00102

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000906

Gnomad NFE exome

AF:

0.00452

Gnomad OTH exome

AF:

0.00290

GnomAD4 exome

AF:

0.00433

AC:

4558

AN:

1052690

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

1516

AN XY:

322506

show subpopulations

African (AFR)

AF:

0.000625

AC:

AN:

25581

American (AMR)

AF:

0.00120

AC:

AN:

35122

Ashkenazi Jewish (ASJ)

AF:

0.000105

AC:

AN:

19118

East Asian (EAS)

AF:

0.00

AC:

AN:

29994

South Asian (SAS)

AF:

0.00392

AC:

208

AN:

53048

European-Finnish (FIN)

AF:

0.000999

AC:

AN:

40049

Middle Eastern (MID)

AF:

0.00623

AC:

AN:

4013

European-Non Finnish (NFE)

AF:

0.00507

AC:

4060

AN:

801124

Other (OTH)

AF:

0.00370

AC:

165

AN:

44641

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

137

275

412

550

687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

162

324

486

648

810

<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:

0.00297

AC:

332

AN:

111823

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

AN XY:

34019

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

30822

American (AMR)

AF:

0.00247

AC:

AN:

10525

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00420

AC:

AN:

2618

European-Finnish (FIN)

AF:

0.000657

AC:

AN:

6087

Middle Eastern (MID)

AF:

0.0183

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00485

AC:

258

AN:

53158

Other (OTH)

AF:

0.00398

AC:

AN:

1507

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

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:

0.00386

Hom.:

Bravo

AF:

0.00267

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

5.5

(source)

DANN

Benign

0.61

PhyloP100

0.21

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over