rs77587352

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001080413.3(NOBOX):c.271G>T(p.Gly91Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,611,800 control chromosomes in the GnomAD database, including 41 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G91E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0078 ( 21 hom., cov: 33)

Exomes 𝑓: 0.00084 ( 20 hom. )

Consequence

NOBOX
NM_001080413.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1B:2

Conservation

PhyloP100: -0.0900

Publications

18 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004914403).

BP6

Variant 7-144401890-C-A is Benign according to our data. Variant chr7-144401890-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167874.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00784 (1194/152240) while in subpopulation AFR AF = 0.0268 (1113/41532). AF 95% confidence interval is 0.0255. There are 21 homozygotes in GnomAd4. There are 585 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1194 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOBOX	NM_001080413.3 link	c.271G>T	p.Gly91Trp	missense_variant	Exon 3 of 10	ENST00000467773.1	NP_001073882.3	O60393-1
NOBOX	XM_017011742.3 link	c.271G>T	p.Gly91Trp	missense_variant	Exon 3 of 10		XP_016867231.1	O60393-2
NOBOX	NM_001436401.1 link	c.38-293G>T		intron_variant	Intron 1 of 7		NP_001423330.1
NOBOX	NM_001436402.1 link	c.38-1578G>T		intron_variant	Intron 1 of 6		NP_001423331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOBOX	ENST00000467773.1 link	c.271G>T	p.Gly91Trp	missense_variant	Exon 3 of 10	5	NM_001080413.3	ENSP00000419457.1	O60393-1
NOBOX	ENST00000483238.5 link	c.271G>T	p.Gly91Trp	missense_variant	Exon 3 of 10	5		ENSP00000419565.1	O60393-2
NOBOX	ENST00000645489.1 link	c.38-293G>T		intron_variant	Intron 1 of 7			ENSP00000496732.1	A0A2R8Y8C8
NOBOX	ENST00000643164.1 link	c.38-1578G>T		intron_variant	Intron 1 of 6			ENSP00000495343.1	A0A2R8Y683

Frequencies

GnomAD3 genomes

AF:

0.00784

AC:

1192

AN:

152122

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.00214

AC:

533

AN:

248636

AF XY:

0.00156

show subpopulations

Gnomad AFR exome

AF:

0.0268

Gnomad AMR exome

AF:

0.00270

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000124

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000841

AC:

1228

AN:

1459560

Hom.:

Cov.:

AF XY:

0.000733

AC XY:

532

AN XY:

726210

show subpopulations

African (AFR)

AF:

0.0246

AC:

821

AN:

33422

American (AMR)

AF:

0.00293

AC:

131

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39686

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86144

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.000521

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.000130

AC:

144

AN:

1110034

Other (OTH)

AF:

0.00206

AC:

124

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

105

157

210

262

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00784

AC:

1194

AN:

152240

Hom.:

Cov.:

AF XY:

0.00786

AC XY:

585

AN XY:

74440

show subpopulations

African (AFR)

AF:

0.0268

AC:

1113

AN:

41532

American (AMR)

AF:

0.00359

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.000414

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000176

AC:

AN:

68018

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

108

162

216

270

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00318

Hom.:

Bravo

AF:

0.00877

ESP6500AA

AF:

0.0293

AC:

110

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.00241

AC:

291

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Premature ovarian failure 5

Pathogenic:2

Dec 16, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 06, 2020

Reproductive Health Research and Development, BGI Genomics

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

NM_001080413.3:c.271G>T in the NOBOX gene has an allele frequency of 0.028 in African subpopulation in the gnomAD database. The NOBOX c.271G>T (p.Gly91Trp) variant has been identified in five individuals affected with primary ovarian insufficiency (PMID: 25514101; 21837770). Functional studies of NOBOX variants revealed that p.Gly91Trp was deleterious for protein function (PMID: 25514101). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PP4; PS4_Supporting. -

not provided

Uncertain:1Benign:1

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 14, 2020

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate impaired autophagosomal degradation and decreased or defective transcriptional activity (Ferrari et al., 2016; Bouilly et al., 2011).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33095795, 31589614, 31293321, 21837770, 27798098, 26848058, 25514101) -

not specified

Benign:1

Oct 28, 2020

H3Africa Consortium

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.061, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.035

.;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.062

LIST_S2

Benign

0.46

T;T

MetaRNN

Benign

0.0049

T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

0.34

N;N

PhyloP100

-0.090

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.40

N;N

REVEL

Uncertain

0.33

Sift

Benign

0.15

T;T

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

.;D

Vest4

0.79

MVP

0.88

MPC

0.025

ClinPred

0.030

GERP RS

-2.0

Varity_R

0.052

gMVP

0.036

Mutation Taster

=97/3

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs77587352

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