rs2525702

chr7-144398975-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080413.3(NOBOX):c.1444G>A(p.Gly482Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.167 in 1,565,842 control chromosomes in the GnomAD database, including 23,403 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2492 hom., cov: 30)
  • Exomes 𝑓: 0.17 (20911 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.314

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005823463).
• BP6: Variant 7-144398975-C-T is Benign according to our data. Variant chr7-144398975-C-T is described in ClinVar as [Benign]. Clinvar id is 138535.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOBOX	NM_001080413.3	c.1444G>A	p.Gly482Ser	missense_variant	8/10	ENST00000467773.1
NOBOX	XM_017011742.3	c.1348G>A	p.Gly450Ser	missense_variant	8/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOBOX	ENST00000467773.1	c.1444G>A	p.Gly482Ser	missense_variant	8/10	5	NM_001080413.3
NOBOX	ENST00000483238.5	c.1348G>A	p.Gly450Ser	missense_variant	8/10	5		A2
NOBOX	ENST00000645489.1	c.1093G>A	p.Gly365Ser	missense_variant	6/8			P2
NOBOX	ENST00000643164.1	c.541G>A	p.Gly181Ser	missense_variant	5/7

Frequencies

GnomAD3 genomes AF: 0.173 AC: 26259 AN: 151900 Hom.: 2489 Cov.: 30

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.410

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.171

Gnomad OTH AF: 0.143

GnomAD3 exomes AF: 0.160 AC: 28908 AN: 181118 Hom.: 2560 AF XY: 0.165 AC XY: 15993 AN XY: 97100

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.147

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00920

Gnomad SAS exome AF: 0.225

Gnomad FIN exome AF: 0.153

Gnomad NFE exome AF: 0.169

Gnomad OTH exome AF: 0.151

GnomAD4 exome AF: 0.167 AC: 235521 AN: 1413822 Hom.: 20911 Cov.: 31 AF XY: 0.169 AC XY: 117890 AN XY: 699238

Gnomad4 AFR exome AF: 0.212

Gnomad4 AMR exome AF: 0.143

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.0107

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.173 AC: 26299 AN: 152020 Hom.: 2492 Cov.: 30 AF XY: 0.171 AC XY: 12740 AN XY: 74302

Gnomad4 AFR AF: 0.213

Gnomad4 AMR AF: 0.124

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.171

Gnomad4 OTH AF: 0.143

Alfa AF: 0.162 Hom.: 3651

Bravo AF: 0.169

TwinsUK AF: 0.165 AC: 610

ALSPAC AF: 0.163 AC: 629

ESP6500AA AF: 0.214 AC: 809

ESP6500EA AF: 0.161 AC: 1323

ExAC AF: 0.138 AC: 16304

Asia WGS AF: 0.139 AC: 485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Premature ovarian failure 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 19, 2014

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.53
Cadd	Benign	14
Dann	Uncertain	0.99
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.65	T;T;T;T
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.28	T
Polyphen		0.16	.;.;B;.
Vest4		0.094, 0.075
MPC		0.026
ClinPred		0.012	T
GERP RS		3.4
Varity_R		0.042
gMVP		0.18

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

LitVar

Other links and lift over

dbSNP: rs2525702; hg19: chr7-144096068; COSMIC: COSV56193464;