7-144397490-G-A

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.1826C>T(p.Pro609Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000514 in 1,536,732 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P609P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 4 hom. )

Consequence

NOBOX
NM_001080413.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:3

Conservation

PhyloP100: 4.17

Publications

0 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=0.010829002).

BP6

Variant 7-144397490-G-A is Benign according to our data. Variant chr7-144397490-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 791163.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1, Likely_benign=2}.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00135 (205/152328) while in subpopulation AFR AF = 0.00397 (165/41570). AF 95% confidence interval is 0.00347. There are 1 homozygotes in GnomAd4. There are 98 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 205 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOBOX	NM_001080413.3 link	c.1826C>T	p.Pro609Leu	missense_variant	Exon 10 of 10	ENST00000467773.1	NP_001073882.3	O60393-1
NOBOX	NM_001436401.1 link	c.1475C>T	p.Pro492Leu	missense_variant	Exon 8 of 8		NP_001423330.1
NOBOX	NM_001436402.1 link	c.923C>T	p.Pro308Leu	missense_variant	Exon 7 of 7		NP_001423331.1
NOBOX	XM_017011742.3 link	c.1730C>T	p.Pro577Leu	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.1826C>T	p.Pro609Leu	missense_variant	Exon 10 of 10	5	NM_001080413.3	ENSP00000419457.1	O60393-1
NOBOX	ENST00000483238.5 link	c.1730C>T	p.Pro577Leu	missense_variant	Exon 10 of 10	5		ENSP00000419565.1	O60393-2
NOBOX	ENST00000645489.1 link	c.1475C>T	p.Pro492Leu	missense_variant	Exon 8 of 8			ENSP00000496732.1	A0A2R8Y8C8
NOBOX	ENST00000643164.1 link	c.*21C>T		downstream_gene_variant				ENSP00000495343.1	A0A2R8Y683

Frequencies

GnomAD3 genomes

AF:

0.00135

AC:

205

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00398

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000523

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00124

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000309

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000850

AC:

118

AN:

138742

AF XY:

0.000872

show subpopulations

Gnomad AFR exome

AF:

0.00403

Gnomad AMR exome

AF:

0.000448

Gnomad ASJ exome

AF:

0.000599

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000270

Gnomad OTH exome

AF:

0.00167

GnomAD4 exome

AF:

0.000423

AC:

585

AN:

1384404

Hom.:

Cov.:

AF XY:

0.000492

AC XY:

336

AN XY:

683064

show subpopulations

African (AFR)

AF:

0.00408

AC:

129

AN:

31580

American (AMR)

AF:

0.000421

AC:

AN:

35670

Ashkenazi Jewish (ASJ)

AF:

0.000676

AC:

AN:

25148

East Asian (EAS)

AF:

0.00

AC:

AN:

35718

South Asian (SAS)

AF:

0.00221

AC:

175

AN:

79210

European-Finnish (FIN)

AF:

0.0000286

AC:

AN:

34988

Middle Eastern (MID)

AF:

0.00281

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.000182

AC:

196

AN:

1078510

Other (OTH)

AF:

0.000622

AC:

AN:

57886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

114

143

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00135

AC:

205

AN:

152328

Hom.:

Cov.:

AF XY:

0.00132

AC XY:

AN XY:

74484

show subpopulations

African (AFR)

AF:

0.00397

AC:

165

AN:

41570

American (AMR)

AF:

0.000523

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00124

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000309

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00135

Hom.:

Bravo

AF:

0.00145

ESP6500AA

AF:

0.00361

AC:

ESP6500EA

AF:

0.000629

AC:

ExAC

AF:

0.00124

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:2

Oct 24, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Apr 19, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported as one of many candidate variants in a 46,XX male patient with inguinal testes, micropenis and hypospadias (Knarston K. 2018 https://minerva-access.unimelb.edu.au/handle/11343/221695); variant maternally inherited; 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: Knarston2018[Thesis]) -

Inborn genetic diseases

Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1826C>T (p.P609L) alteration is located in exon 10 (coding exon 10) of the NOBOX gene. This alteration results from a C to T substitution at nucleotide position 1826, causing the proline (P) at amino acid position 609 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Premature ovarian failure 5

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;.;T

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.70

T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.10

MutationAssessor

Benign

1.5

.;.;L

PhyloP100

4.2

PrimateAI

Benign

0.32

PROVEAN

Uncertain

-2.6

.;D;D

REVEL

Benign

0.26

Sift

Uncertain

0.0010

.;D;D

Sift4G

Uncertain

0.015

.;D;D

Vest4

0.23, 0.17

MVP

0.82

MPC

0.14

ClinPred

0.038

GERP RS

3.6

Varity_R

0.043

gMVP

0.13

Mutation Taster

=91/9

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

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7-144397490-G-A

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