rs193303104

Positions:

• chr7-144399863-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_001080413.3(NOBOX):​c.1048G>T​(p.Val350Leu) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NOBOX NM_001080413.3 missense, splice_region
• Scores: Splicing: ADA: 0.9992
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.08

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 7-144399863-C-A is Pathogenic according to our data. Variant chr7-144399863-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 167877.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOBOX	NM_001080413.3	c.1048G>T	p.Val350Leu	missense_variant, splice_region_variant	6/10	ENST00000467773.1	NP_001073882.3
NOBOX	XM_017011742.3	c.952G>T	p.Val318Leu	missense_variant, splice_region_variant	6/10		XP_016867231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOBOX	ENST00000467773.1	c.1048G>T	p.Val350Leu	missense_variant, splice_region_variant	6/10	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5	c.952G>T	p.Val318Leu	missense_variant, splice_region_variant	6/10	5		ENSP00000419565.1
NOBOX	ENST00000645489.1	c.697G>T	p.Val233Leu	missense_variant, splice_region_variant	4/8			ENSP00000496732.1
NOBOX	ENST00000643164.1	c.145G>T	p.Val49Leu	missense_variant, splice_region_variant	3/7			ENSP00000495343.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Premature ovarian failure 5 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.48	D
BayesDel_noAF	Pathogenic	0.45
CADD	Pathogenic	36
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;.;T;.
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Pathogenic	0.98	D;D;T;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	.;.;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	.;D;N;.
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	.;D;D;.
Sift4G	Uncertain	0.0090	.;D;D;.
Polyphen		1.0	.;.;D;.
Vest4		0.76, 0.75
MutPred		0.83		.;.;Loss of MoRF binding (P = 0.1222);.;
MVP		0.98
MPC		0.19
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.25
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.89
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.67		Position offset: 26

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs193303104; hg19: chr7-144096956;