rs193303104

Variant names:

• chr7-144399863-C-A
• rs193303104
• NM_001080413.3:c.1048G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3 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
• Publications: 7 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 7-144399863-C-A is Pathogenic according to our data. Variant chr7-144399863-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 167877.Status of the report is no_assertion_criteria_provided, 0 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOBOX	NM_001080413.3	MANE Select	c.1048G>T	p.Val350Leu	missense splice_region	Exon 6 of 10	NP_001073882.3
	NOBOX	NM_001436401.1		c.697G>T	p.Val233Leu	missense splice_region	Exon 4 of 8	NP_001423330.1
	NOBOX	NM_001436402.1		c.145G>T	p.Val49Leu	missense splice_region	Exon 3 of 7	NP_001423331.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOBOX	ENST00000467773.1	TSL:5 MANE Select	c.1048G>T	p.Val350Leu	missense splice_region	Exon 6 of 10	ENSP00000419457.1
	NOBOX	ENST00000483238.5	TSL:5	c.952G>T	p.Val318Leu	missense splice_region	Exon 6 of 10	ENSP00000419565.1
	NOBOX	ENST00000645489.1		c.697G>T	p.Val233Leu	missense splice_region	Exon 4 of 8	ENSP00000496732.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		4.1
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.9	D
REVEL	Pathogenic	0.83
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.76
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
Mutation Taster		=16/84	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193303104; hg19: chr7-144096956;