rs886062037

Variant names:

• chr7-144397416-G-T
• rs886062037
• NM_001080413.3:c.1900C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001080413.3(NOBOX):​c.1900C>A​(p.Pro634Thr) 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 1,384,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P634L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.482
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.032445163).

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.1900C>A	p.Pro634Thr	missense	Exon 10 of 10	NP_001073882.3	O60393-1
	NOBOX	NM_001436401.1		c.1549C>A	p.Pro517Thr	missense	Exon 8 of 8	NP_001423330.1	A0A2R8Y8C8
	NOBOX	NM_001436402.1		c.997C>A	p.Pro333Thr	missense	Exon 7 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.1900C>A	p.Pro634Thr	missense	Exon 10 of 10	ENSP00000419457.1	O60393-1
	NOBOX	ENST00000645489.2		c.1549C>A	p.Pro517Thr	missense	Exon 8 of 8	ENSP00000496732.1
	NOBOX	ENST00000643164.2		c.997C>A	p.Pro333Thr	missense	Exon 7 of 7	ENSP00000495343.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000713 AC: 1 AN: 140234 AF XY: 0.0000133

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000942

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384932 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 683398

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35734

South Asian (SAS) AF: 0.00 AC: 0 AN: 79234

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078880

Other (OTH) AF: 0.00 AC: 0 AN: 57914

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Premature ovarian failure 5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	1.2
DANN	Benign	0.38
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0083	N
LIST_S2	Benign	0.36	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.032	T
MetaSVM	Benign	-0.68	T
MutationAssessor	Benign	-1.4	N
PhyloP100		0.48
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.60	N
REVEL	Benign	0.18
Sift	Benign	0.75	T
Sift4G	Benign	0.56	T
Vest4		0.052
MutPred		0.12		Loss of catalytic residue at P634 (P = 0.046)
MVP		0.34
MPC		0.023
ClinPred		0.030	T
GERP RS		1.6
Varity_R		0.023
gMVP		0.10
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs886062037; hg19: chr7-144094509; COSMIC: COSV56192999; COSMIC: COSV56192999;