7-144399847-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PP3_StrongBS2

The NM_001080413.3(NOBOX):c.1064G>A(p.Arg355His) variant causes a missense change. The variant allele was found at a frequency of 0.0000912 in 1,611,620 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000072 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000093 ( 1 hom. )

Consequence

NOBOX
NM_001080413.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 5.68

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.94

BS2

High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOBOX	NM_001080413.3 link	c.1064G>A	p.Arg355His	missense_variant	Exon 6 of 10	ENST00000467773.1	NP_001073882.3	O60393-1
NOBOX	XM_017011742.3 link	c.968G>A	p.Arg323His	missense_variant	Exon 6 of 10		XP_016867231.1	O60393-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOBOX	ENST00000467773.1 link	c.1064G>A	p.Arg355His	missense_variant	Exon 6 of 10	5	NM_001080413.3	ENSP00000419457.1	O60393-1
NOBOX	ENST00000483238.5 link	c.968G>A	p.Arg323His	missense_variant	Exon 6 of 10	5		ENSP00000419565.1	O60393-2
NOBOX	ENST00000645489.1 link	c.713G>A	p.Arg238His	missense_variant	Exon 4 of 8			ENSP00000496732.1	A0A2R8Y8C8
NOBOX	ENST00000643164.1 link	c.161G>A	p.Arg54His	missense_variant	Exon 3 of 7			ENSP00000495343.1	A0A2R8Y683

Frequencies

GnomAD3 genomes

AF:

0.0000723

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000189

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000157

AC:

AN:

247876

Hom.:

AF XY:

0.000141

AC XY:

AN XY:

134482

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00110

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000364

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.0000978

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.0000932

AC:

136

AN:

1459348

Hom.:

Cov.:

AF XY:

0.0000965

AC XY:

AN XY:

725498

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000920

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000268

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.0000649

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000722

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.0000806

AC XY:

AN XY:

74458

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000387

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.000189

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000196

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.000190

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Premature ovarian failure 5

Pathogenic:1Benign:1

Oct 20, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Sep 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Genetic non-acquired premature ovarian failure

Pathogenic:1

Oct 01, 2019

Center for Reproductive Medicine, Shandong Provincial Hospital Affiliated to Shandong University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

not provided

Uncertain:1

Feb 10, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in the heterozygous state in a patient with primary ovarian failure in published literature (Qin et al., 2007); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 31589614, 31293321, 17701902) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.51

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

.;.;D;.

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.87

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Pathogenic

0.54

MetaRNN

Pathogenic

0.94

D;D;D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

.;.;M;.

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-4.8

.;D;D;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

.;D;D;.

Sift4G

Pathogenic

0.0

.;D;D;.

Polyphen

1.0

.;.;D;.

Vest4

0.92, 0.77

MutPred

0.91

.;.;Loss of disorder (P = 0.0885);.;

MVP

0.98

MPC

0.20

ClinPred

0.31

GERP RS

4.7

Varity_R

0.72

gMVP

0.59

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over