rs77587352

chr7-144401890-C-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001080413.3(NOBOX):c.271G>T(p.Gly91Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0015 in 1,611,800 control chromosomes in the GnomAD database, including 41 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0078 (21 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (20 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:2
• Conservation: PhyloP100: -0.0900

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004914403).
• BP6: Variant 7-144401890-C-A is Benign according to our data. Variant chr7-144401890-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 167874.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00784 (1194/152240) while in subpopulation AFR AF= 0.0268 (1113/41532). AF 95% confidence interval is 0.0255. There are 21 homozygotes in gnomad4. There are 585 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1192 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOBOX	NM_001080413.3	c.271G>T	p.Gly91Trp	missense_variant	3/10	ENST00000467773.1
NOBOX	XM_017011742.3	c.271G>T	p.Gly91Trp	missense_variant	3/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOBOX	ENST00000467773.1	c.271G>T	p.Gly91Trp	missense_variant	3/10	5	NM_001080413.3
NOBOX	ENST00000483238.5	c.271G>T	p.Gly91Trp	missense_variant	3/10	5		A2
NOBOX	ENST00000643164.1	c.38-1578G>T		intron_variant
NOBOX	ENST00000645489.1	c.38-293G>T		intron_variant				P2

Frequencies

GnomAD3 genomes AF: 0.00784 AC: 1192 AN: 152122 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.0268

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000176

Gnomad OTH AF: 0.00573

GnomAD3 exomes AF: 0.00214 AC: 533 AN: 248636 Hom.: 11 AF XY: 0.00156 AC XY: 211 AN XY: 134950

Gnomad AFR exome AF: 0.0268

Gnomad AMR exome AF: 0.00270

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00149

GnomAD4 exome AF: 0.000841 AC: 1228 AN: 1459560 Hom.: 20 Cov.: 29 AF XY: 0.000733 AC XY: 532 AN XY: 726210

Gnomad4 AFR exome AF: 0.0246

Gnomad4 AMR exome AF: 0.00293

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000130

Gnomad4 OTH exome AF: 0.00206

GnomAD4 genome AF: 0.00784 AC: 1194 AN: 152240 Hom.: 21 Cov.: 33 AF XY: 0.00786 AC XY: 585 AN XY: 74440

Gnomad4 AFR AF: 0.0268

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000176

Gnomad4 OTH AF: 0.00567

Alfa AF: 0.00132 Hom.: 5

Bravo AF: 0.00877

ESP6500AA AF: 0.0293 AC: 110

ESP6500EA AF: 0.000122 AC: 1

ExAC AF: 0.00241 AC: 291

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Premature ovarian failure 5 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 16, 2014	- -
Likely pathogenic, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NM_001080413.3:c.271G>T in the NOBOX gene has an allele frequency of 0.028 in African subpopulation in the gnomAD database. The NOBOX c.271G>T (p.Gly91Trp) variant has been identified in five individuals affected with primary ovarian insufficiency (PMID: 25514101; 21837770). Functional studies of NOBOX variants revealed that p.Gly91Trp was deleterious for protein function (PMID: 25514101). Taken together, we interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS3; PP4; PS4_Supporting. -

not provided Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 14, 2020	Published functional studies demonstrate impaired autophagosomal degradation and decreased or defective transcriptional activity (Ferrari et al., 2016; Bouilly et al., 2011).; In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 33095795, 31589614, 31293321, 21837770, 27798098, 26848058, 25514101) -

not specified Benign:1

Benign, criteria provided, single submitter

research

H3Africa Consortium

Oct 28, 2020

While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.061, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	12
Dann	Benign	0.63
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.062	N
LIST_S2	Benign	0.46	T;T
MetaRNN	Benign	0.0049	T;T
MetaSVM	Uncertain	-0.25	T
MutationAssessor	Benign	0.34	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.40	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.15	T;T
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	.;D
Vest4		0.79
MVP		0.88
MPC		0.025
ClinPred		0.030	T
GERP RS		-2.0
Varity_R		0.052
gMVP		0.036

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

LitVar

Other links and lift over

dbSNP: rs77587352; hg19: chr7-144098983; COSMIC: COSV56195376;