chr7-144397325-T-C

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.1991A>G(p.Lys664Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,537,224 control chromosomes in the GnomAD database, including 1,291 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.030 ( 79 hom., cov: 32)

Exomes 𝑓: 0.040 ( 1212 hom. )

Consequence

NOBOX
NM_001080413.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.875

Publications

7 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=0.0027282238).

BP6

Variant 7-144397325-T-C is Benign according to our data. Variant chr7-144397325-T-C is described in ClinVar as [Benign]. Clinvar id is 359131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOBOX	NM_001080413.3 link	c.1991A>G	p.Lys664Arg	missense_variant	Exon 10 of 10	ENST00000467773.1	NP_001073882.3	O60393-1
NOBOX	NM_001436401.1 link	c.1640A>G	p.Lys547Arg	missense_variant	Exon 8 of 8		NP_001423330.1
NOBOX	NM_001436402.1 link	c.1088A>G	p.Lys363Arg	missense_variant	Exon 7 of 7		NP_001423331.1
NOBOX	XM_017011742.3 link	c.1895A>G	p.Lys632Arg	missense_variant	Exon 10 of 10		XP_016867231.1	O60393-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOBOX	ENST00000467773.1 link	c.1991A>G	p.Lys664Arg	missense_variant	Exon 10 of 10	5	NM_001080413.3	ENSP00000419457.1	O60393-1
NOBOX	ENST00000483238.5 link	c.1895A>G	p.Lys632Arg	missense_variant	Exon 10 of 10	5		ENSP00000419565.1	O60393-2
NOBOX	ENST00000645489.1 link	c.1640A>G	p.Lys547Arg	missense_variant	Exon 8 of 8			ENSP00000496732.1	A0A2R8Y8C8
NOBOX	ENST00000643164.1 link	c.*186A>G		downstream_gene_variant				ENSP00000495343.1	A0A2R8Y683

Frequencies

GnomAD3 genomes

AF:

0.0301

AC:

4575

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00847

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.0332

Gnomad ASJ

AF:

0.0524

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0104

Gnomad FIN

AF:

0.0441

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0425

Gnomad OTH

AF:

0.0445

GnomAD2 exomes

AF:

0.0304

AC:

4307

AN:

141844

AF XY:

0.0298

show subpopulations

Gnomad AFR exome

AF:

0.00763

Gnomad AMR exome

AF:

0.0243

Gnomad ASJ exome

AF:

0.0528

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0420

Gnomad NFE exome

AF:

0.0439

Gnomad OTH exome

AF:

0.0404

GnomAD4 exome

AF:

0.0395

AC:

54725

AN:

1384932

Hom.:

1212

Cov.:

AF XY:

0.0393

AC XY:

26867

AN XY:

683396

show subpopulations

African (AFR)

AF:

0.00684

AC:

216

AN:

31594

American (AMR)

AF:

0.0266

AC:

950

AN:

35696

Ashkenazi Jewish (ASJ)

AF:

0.0559

AC:

1407

AN:

25182

East Asian (EAS)

AF:

0.0000840

AC:

AN:

35734

South Asian (SAS)

AF:

0.0125

AC:

992

AN:

79236

European-Finnish (FIN)

AF:

0.0453

AC:

1584

AN:

35000

Middle Eastern (MID)

AF:

0.0662

AC:

377

AN:

5696

European-Non Finnish (NFE)

AF:

0.0435

AC:

46944

AN:

1078878

Other (OTH)

AF:

0.0389

AC:

2252

AN:

57916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

3082

6165

9247

12330

15412

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0300

AC:

4572

AN:

152292

Hom.:

Cov.:

AF XY:

0.0301

AC XY:

2244

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00847

AC:

352

AN:

41560

American (AMR)

AF:

0.0332

AC:

508

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0524

AC:

182

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0102

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0441

AC:

468

AN:

10620

Middle Eastern (MID)

AF:

0.0646

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0425

AC:

2889

AN:

68014

Other (OTH)

AF:

0.0440

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

241

481

722

962

1203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0391

Hom.:

255

Bravo

AF:

0.0294

TwinsUK

AF:

0.0456

AC:

169

ALSPAC

AF:

0.0418

AC:

161

ESP6500AA

AF:

0.00795

AC:

ESP6500EA

AF:

0.0475

AC:

151

ExAC

AF:

0.0235

AC:

567

Asia WGS

AF:

0.00693

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Premature ovarian failure 5

Benign:1

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

Jan 12, 2016

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

0.071

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.19

(source)

DANN

Benign

0.71

DEOGEN2

Benign

0.033

.;.;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0097

LIST_S2

Benign

0.51

T;T;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.69

.;.;N

PhyloP100

-0.88

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.30

.;N;N

REVEL

Benign

0.11

Sift

Benign

0.066

.;T;T

Sift4G

Benign

0.26

.;T;T

Vest4

0.027, 0.043

MPC

0.021

ClinPred

0.0077

GERP RS

-7.2

Varity_R

0.025

gMVP

0.052

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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chr7-144397325-T-C

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