NM_001080413.3:c.1064G>A

Variant names:

• chr7-144399847-C-T
• rs201947677
• NM_001080413.3:c.1064G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 4P and 5B. PP3_Strong BP6 BS2

The NM_001080413.3(NOBOX):​c.1064G>A​(p.Arg355His) variant causes a missense change. The variant allele was found at a frequency of 0.0000912 in 1,611,620 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R355P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000093 (1 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1 B:1
• Conservation: PhyloP100: 5.68
• Publications: 18 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: Likely_benign. The variant received -1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94
• BP6: Variant 7-144399847-C-T is Benign according to our data. Variant chr7-144399847-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1083.
• BS2: High AC in GnomAd4 at 11 AD gene.

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.1064G>A	p.Arg355His	missense	Exon 6 of 10	NP_001073882.3	O60393-1
	NOBOX	NM_001436401.1		c.713G>A	p.Arg238His	missense	Exon 4 of 8	NP_001423330.1	A0A2R8Y8C8
	NOBOX	NM_001436402.1		c.161G>A	p.Arg54His	missense	Exon 3 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.1064G>A	p.Arg355His	missense	Exon 6 of 10	ENSP00000419457.1	O60393-1
	NOBOX	ENST00000645489.2		c.713G>A	p.Arg238His	missense	Exon 4 of 8	ENSP00000496732.1
	NOBOX	ENST00000643164.2		c.161G>A	p.Arg54His	missense	Exon 3 of 7	ENSP00000495343.2

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152154 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000157 AC: 39 AN: 247876 AF XY: 0.000141

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00110

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.000332

GnomAD4 exome AF: 0.0000932 AC: 136 AN: 1459348 Hom.: 1 Cov.: 32 AF XY: 0.0000965 AC XY: 70 AN XY: 725498

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.000920 AC: 24 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.000268 AC: 23 AN: 85972

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53342

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000649 AC: 72 AN: 1110216

Other (OTH) AF: 0.000116 AC: 7 AN: 60262

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152272 Hom.: 0 Cov.: 33 AF XY: 0.0000806 AC XY: 6 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41540

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000387 AC: 2 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000841 Hom.: 0

Bravo AF: 0.0000529

ExAC AF: 0.000190 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	1	Premature ovarian failure 5 (2)
1	-	-	Genetic non-acquired premature ovarian failure (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		5.7
PrimateAI	Uncertain	0.59	T
PROVEAN	Pathogenic	-4.8	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.91		Loss of disorder (P = 0.0885)
MVP		0.98
MPC		0.20
ClinPred		0.31	T
GERP RS		4.7
Varity_R		0.72
gMVP		0.59
Mutation Taster		=78/22	polymorphism

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: rs201947677; hg19: chr7-144096940; COSMIC: COSV56196295;