Genetic Variant NOBOX:p.Pro654Leu (chr7-144397355-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001080413.3(NOBOX):c.1961C>T(p.Pro654Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

NOBOX
NM_001080413.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.565

Publications

1 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20220509).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOBOX	NM_001080413.3 link	c.1961C>T	p.Pro654Leu	missense_variant	Exon 10 of 10	ENST00000467773.1	NP_001073882.3	O60393-1
NOBOX	NM_001436401.1 link	c.1610C>T	p.Pro537Leu	missense_variant	Exon 8 of 8		NP_001423330.1
NOBOX	NM_001436402.1 link	c.1058C>T	p.Pro353Leu	missense_variant	Exon 7 of 7		NP_001423331.1
NOBOX	XM_017011742.3 link	c.1865C>T	p.Pro622Leu	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.1961C>T	p.Pro654Leu	missense_variant	Exon 10 of 10	5	NM_001080413.3	ENSP00000419457.1	O60393-1
NOBOX	ENST00000483238.5 link	c.1865C>T	p.Pro622Leu	missense_variant	Exon 10 of 10	5		ENSP00000419565.1	O60393-2
NOBOX	ENST00000645489.1 link	c.1610C>T	p.Pro537Leu	missense_variant	Exon 8 of 8			ENSP00000496732.1	A0A2R8Y8C8
NOBOX	ENST00000643164.1 link	c.*156C>T		downstream_gene_variant				ENSP00000495343.1	A0A2R8Y683

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.22e-7

AC:

AN:

1384928

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

683394

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31594

American (AMR)

AF:

0.00

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00

AC:

AN:

79234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

35000

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078876

Other (OTH)

AF:

0.0000173

AC:

AN:

57914

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Feb 21, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1961C>T (p.P654L) 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 1961, causing the proline (P) at amino acid position 654 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

0.0015

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.38

.;.;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.035

LIST_S2

Benign

0.70

T;T;T

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Uncertain

-0.082

MutationAssessor

Benign

1.9

.;.;L

PhyloP100

0.56

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-4.0

.;D;D

REVEL

Benign

0.24

Sift

Uncertain

0.0010

.;D;D

Sift4G

Benign

0.084

.;T;T

Vest4

0.22, 0.18

MutPred

0.14

.;.;Loss of methylation at R653 (P = 0.1209);

MVP

0.71

MPC

0.10

ClinPred

0.97

GERP RS

2.5

Varity_R

0.051

gMVP

0.11

Mutation Taster

=98/2

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over