chr7-144399847-C-G

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001080413.3(NOBOX):​c.1064G>C​(p.Arg355Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,459,348 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. R355H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOBOX	NM_001080413.3	c.1064G>C	p.Arg355Pro	missense_variant	Exon 6 of 10	ENST00000467773.1	NP_001073882.3
NOBOX	NM_001436401.1	c.713G>C	p.Arg238Pro	missense_variant	Exon 4 of 8		NP_001423330.1
NOBOX	NM_001436402.1	c.161G>C	p.Arg54Pro	missense_variant	Exon 3 of 7		NP_001423331.1
NOBOX	XM_017011742.3	c.968G>C	p.Arg323Pro	missense_variant	Exon 6 of 10		XP_016867231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOBOX	ENST00000467773.1	c.1064G>C	p.Arg355Pro	missense_variant	Exon 6 of 10	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5	c.968G>C	p.Arg323Pro	missense_variant	Exon 6 of 10	5		ENSP00000419565.1
NOBOX	ENST00000645489.1	c.713G>C	p.Arg238Pro	missense_variant	Exon 4 of 8			ENSP00000496732.1
NOBOX	ENST00000643164.1	c.161G>C	p.Arg54Pro	missense_variant	Exon 3 of 7			ENSP00000495343.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000403 AC: 1 AN: 247876 AF XY: 0.00000744

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459348 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 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: 0.00 AC: 0 AN: 26080

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 85972

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1110216

Other (OTH) AF: 0.00 AC: 0 AN: 60262

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Premature ovarian failure 5 Uncertain:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.74	.;.;D;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Pathogenic	0.60	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.6	.;.;M;.
PhyloP100		5.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-6.8	.;D;D;.
REVEL	Pathogenic	0.94
Sift	Uncertain	0.0010	.;D;D;.
Sift4G	Pathogenic	0.0	.;D;D;.
Polyphen		1.0	.;.;D;.
Vest4		0.85, 0.79
MutPred		0.86		.;.;Gain of glycosylation at R355 (P = 0.0296);.;
MVP		0.98
MPC		0.21
ClinPred		0.99	D
GERP RS		4.7
Varity_R		0.94
gMVP		0.78
Mutation Taster		=59/41	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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;