rs2525702

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001080413.3(NOBOX):c.1444G>A(p.Gly482Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,565,842 control chromosomes in the GnomAD database, including 23,403 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.17 ( 2492 hom., cov: 30)

Exomes 𝑓: 0.17 ( 20911 hom. )

Consequence

NOBOX
NM_001080413.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.314

Publications

17 publications found

Variant links:

Genes affected

NOBOX (HGNC:22448): (NOBOX oogenesis homeobox) This homeobox gene encodes a transcription factor that is thought to play a role in oogenesis. In mice, it is essential for folliculogenesis and regulation of oocyte-specific genes. Defects in this gene result in premature ovarian failure type 5.[provided by RefSeq, May 2011]

NOBOX Gene-Disease associations (from GenCC):

premature ovarian failure 5
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

NOBOX 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 (MetaRNN=0.005823463).

BP6

Variant 7-144398975-C-T is Benign according to our data. Variant chr7-144398975-C-T is described in ClinVar as Benign. ClinVar VariationId is 138535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NOBOX	NM_001080413.3 link	c.1444G>A	p.Gly482Ser	missense_variant	Exon 8 of 10	ENST00000467773.1	NP_001073882.3
NOBOX	NM_001436401.1 link	c.1093G>A	p.Gly365Ser	missense_variant	Exon 6 of 8		NP_001423330.1
NOBOX	NM_001436402.1 link	c.541G>A	p.Gly181Ser	missense_variant	Exon 5 of 7		NP_001423331.1
NOBOX	XM_017011742.3 link	c.1348G>A	p.Gly450Ser	missense_variant	Exon 8 of 10		XP_016867231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NOBOX	ENST00000467773.1 link	c.1444G>A	p.Gly482Ser	missense_variant	Exon 8 of 10	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5 link	c.1348G>A	p.Gly450Ser	missense_variant	Exon 8 of 10	5		ENSP00000419565.1
NOBOX	ENST00000645489.1 link	c.1093G>A	p.Gly365Ser	missense_variant	Exon 6 of 8			ENSP00000496732.1
NOBOX	ENST00000643164.1 link	c.541G>A	p.Gly181Ser	missense_variant	Exon 5 of 7			ENSP00000495343.1

Frequencies

GnomAD3 genomes

AF:

0.173

AC:

26259

AN:

151900

Hom.:

2489

Cov.:

show subpopulations

Gnomad AFR

AF:

0.213

Gnomad AMI

AF:

0.410

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.109

Gnomad EAS

AF:

0.0114

Gnomad SAS

AF:

0.227

Gnomad FIN

AF:

0.159

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.171

Gnomad OTH

AF:

0.143

GnomAD2 exomes

AF:

0.160

AC:

28908

AN:

181118

AF XY:

0.165

show subpopulations

Gnomad AFR exome

AF:

0.218

Gnomad AMR exome

AF:

0.147

Gnomad ASJ exome

AF:

0.112

Gnomad EAS exome

AF:

0.00920

Gnomad FIN exome

AF:

0.153

Gnomad NFE exome

AF:

0.169

Gnomad OTH exome

AF:

0.151

GnomAD4 exome

AF:

0.167

AC:

235521

AN:

1413822

Hom.:

20911

Cov.:

AF XY:

0.169

AC XY:

117890

AN XY:

699238

show subpopulations

African (AFR)

AF:

0.212

AC:

6868

AN:

32380

American (AMR)

AF:

0.143

AC:

5407

AN:

37842

Ashkenazi Jewish (ASJ)

AF:

0.113

AC:

2862

AN:

25336

East Asian (EAS)

AF:

0.0107

AC:

397

AN:

37126

South Asian (SAS)

AF:

0.224

AC:

18050

AN:

80544

European-Finnish (FIN)

AF:

0.152

AC:

7682

AN:

50500

Middle Eastern (MID)

AF:

0.181

AC:

1032

AN:

5704

European-Non Finnish (NFE)

AF:

0.169

AC:

183822

AN:

1085828

Other (OTH)

AF:

0.161

AC:

9401

AN:

58562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

8679

17357

26036

34714

43393

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6476

12952

19428

25904

32380

<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:

0.173

AC:

26299

AN:

152020

Hom.:

2492

Cov.:

AF XY:

0.171

AC XY:

12740

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.213

AC:

8832

AN:

41450

American (AMR)

AF:

0.124

AC:

1894

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.109

AC:

378

AN:

3470

East Asian (EAS)

AF:

0.0114

AC:

AN:

5158

South Asian (SAS)

AF:

0.227

AC:

1091

AN:

4808

European-Finnish (FIN)

AF:

0.159

AC:

1681

AN:

10574

Middle Eastern (MID)

AF:

0.201

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.171

AC:

11629

AN:

67970

Other (OTH)

AF:

0.143

AC:

302

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1074

2149

3223

4298

5372

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

294

588

882

1176

1470

<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:

0.165

Hom.:

5194

Bravo

AF:

0.169

TwinsUK

AF:

0.165

AC:

610

ALSPAC

AF:

0.163

AC:

629

ESP6500AA

AF:

0.214

AC:

809

ESP6500EA

AF:

0.161

AC:

1323

ExAC

AF:

0.138

AC:

16304

Asia WGS

AF:

0.139

AC:

485

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Premature ovarian failure 5

Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

not specified

Benign:1

May 19, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

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

AlphaMissense

Benign

0.095

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;.;T;.

Eigen

Benign

-0.63

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.095

LIST_S2

Benign

0.65

T;T;T;T

MetaRNN

Benign

0.0058

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;.;L;.

PhyloP100

0.31

PrimateAI

Benign

0.28

PROVEAN

Benign

0.0

.;N;N;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;T;T;.

Sift4G

Pathogenic

0.0

.;T;T;.

Vest4

0.0

ClinPred

0.012

GERP RS

3.4

Varity_R

0.042

gMVP

0.18

Mutation Taster

=98/2

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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