rs2525702

Variant names:

• chr7-144398975-C-T
• rs2525702
• NM_001080413.3:c.1444G>A

Variant summary

Our verdict is Benign. The variant received -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. 14/20 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:4
• Conservation: PhyloP100: 0.314
• Publications: 17 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080413.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOBOX	NM_001080413.3	MANE Select	c.1444G>A	p.Gly482Ser	missense	Exon 8 of 10	NP_001073882.3	O60393-1
	NOBOX	NM_001436401.1		c.1093G>A	p.Gly365Ser	missense	Exon 6 of 8	NP_001423330.1	A0A2R8Y8C8
	NOBOX	NM_001436402.1		c.541G>A	p.Gly181Ser	missense	Exon 5 of 7	NP_001423331.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOBOX	ENST00000467773.1	TSL:5 MANE Select	c.1444G>A	p.Gly482Ser	missense	Exon 8 of 10	ENSP00000419457.1	O60393-1
	NOBOX	ENST00000645489.2		c.1093G>A	p.Gly365Ser	missense	Exon 6 of 8	ENSP00000496732.1
	NOBOX	ENST00000643164.2		c.541G>A	p.Gly181Ser	missense	Exon 5 of 7	ENSP00000495343.2

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

GnomAD2 exomes AF: 0.160 AC: 28908 AN: 181118 AF XY: 0.165

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 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

African (AFR) AF: 0.212 AC: 6868 AN: 32380

American (AMR) AF: 0.143 AC: 5407 AN: 37842

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 2862 AN: 25336

East Asian (EAS) AF: 0.0107 AC: 397 AN: 37126

South Asian (SAS) AF: 0.224 AC: 18050 AN: 80544

European-Finnish (FIN) AF: 0.152 AC: 7682 AN: 50500

Middle Eastern (MID) AF: 0.181 AC: 1032 AN: 5704

European-Non Finnish (NFE) AF: 0.169 AC: 183822 AN: 1085828

Other (OTH) AF: 0.161 AC: 9401 AN: 58562

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

African (AFR) AF: 0.213 AC: 8832 AN: 41450

American (AMR) AF: 0.124 AC: 1894 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.109 AC: 378 AN: 3470

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5158

South Asian (SAS) AF: 0.227 AC: 1091 AN: 4808

European-Finnish (FIN) AF: 0.159 AC: 1681 AN: 10574

Middle Eastern (MID) AF: 0.201 AC: 59 AN: 294

European-Non Finnish (NFE) AF: 0.171 AC: 11629 AN: 67970

Other (OTH) AF: 0.143 AC: 302 AN: 2106

Alfa AF: 0.165 Hom.: 5194

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Premature ovarian failure 5 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
DEOGEN2	Benign	0.064	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.095	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.31
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.040
Sift	Benign	0.11	T
Sift4G	Benign	0.16	T
Polyphen		0.16	B
Vest4		0.094
MPC		0.026
ClinPred		0.012	T
GERP RS		3.4
Varity_R		0.042
gMVP		0.18
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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