7-144397460-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001080413.3(NOBOX):c.1856C>T(p.Pro619Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000705 in 1,536,878 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0037 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00038 ( 3 hom. )

Consequence

NOBOX
NM_001080413.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0110

Publications

6 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 -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004450977).

BP6

Variant 7-144397460-G-A is Benign according to our data. Variant chr7-144397460-G-A is described in ClinVar as [Benign]. Clinvar id is 359134.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00368 (560/152288) while in subpopulation AFR AF = 0.0128 (533/41560). AF 95% confidence interval is 0.0119. There are 0 homozygotes in GnomAd4. There are 253 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 560 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOBOX	NM_001080413.3 link	c.1856C>T	p.Pro619Leu	missense_variant	Exon 10 of 10	ENST00000467773.1	NP_001073882.3	O60393-1
NOBOX	NM_001436401.1 link	c.1505C>T	p.Pro502Leu	missense_variant	Exon 8 of 8		NP_001423330.1
NOBOX	NM_001436402.1 link	c.953C>T	p.Pro318Leu	missense_variant	Exon 7 of 7		NP_001423331.1
NOBOX	XM_017011742.3 link	c.1760C>T	p.Pro587Leu	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.1856C>T	p.Pro619Leu	missense_variant	Exon 10 of 10	5	NM_001080413.3	ENSP00000419457.1	O60393-1
NOBOX	ENST00000483238.5 link	c.1760C>T	p.Pro587Leu	missense_variant	Exon 10 of 10	5		ENSP00000419565.1	O60393-2
NOBOX	ENST00000645489.1 link	c.1505C>T	p.Pro502Leu	missense_variant	Exon 8 of 8			ENSP00000496732.1	A0A2R8Y8C8
NOBOX	ENST00000643164.1 link	c.*51C>T		downstream_gene_variant				ENSP00000495343.1	A0A2R8Y683

Frequencies

GnomAD3 genomes

AF:

0.00366

AC:

557

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00111

AC:

154

AN:

139288

AF XY:

0.000950

show subpopulations

Gnomad AFR exome

AF:

0.0151

Gnomad AMR exome

AF:

0.00118

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000125

Gnomad OTH exome

AF:

0.000952

GnomAD4 exome

AF:

0.000378

AC:

524

AN:

1384590

Hom.:

Cov.:

AF XY:

0.000348

AC XY:

238

AN XY:

683232

show subpopulations

African (AFR)

AF:

0.0124

AC:

391

AN:

31590

American (AMR)

AF:

0.00112

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.0000126

AC:

AN:

79226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34998

Middle Eastern (MID)

AF:

0.000878

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000389

AC:

AN:

1078578

Other (OTH)

AF:

0.000777

AC:

AN:

57890

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

129

161

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00368

AC:

560

AN:

152288

Hom.:

Cov.:

AF XY:

0.00340

AC XY:

253

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0128

AC:

533

AN:

41560

American (AMR)

AF:

0.00111

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68030

Other (OTH)

AF:

0.000474

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

123

154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00542

Hom.:

Bravo

AF:

0.00441

ExAC

AF:

0.00153

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Premature ovarian failure 5

Benign:1

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

3.6

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.12

.;.;T

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.019

LIST_S2

Benign

0.67

T;T;T

MetaRNN

Benign

0.0045

T;T;T

MetaSVM

Benign

-0.37

MutationAssessor

Benign

0.90

.;.;L

PhyloP100

-0.011

PrimateAI

Benign

0.27

PROVEAN

Uncertain

-2.7

.;D;D

REVEL

Benign

0.11

Sift

Benign

0.20

.;T;T

Sift4G

Benign

1.0

.;T;T

Vest4

0.11, 0.083

MVP

0.62

MPC

0.023

ClinPred

0.0095

GERP RS

1.4

Varity_R

0.033

gMVP

0.11

Mutation Taster

=98/2

polymorphism

(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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7-144397460-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