7-144397355-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001080413.3(NOBOX):c.1961C>T(p.Pro654Leu) 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 1,384,928 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: 0.565

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20220509).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOBOX	NM_001080413.3	c.1961C>T	p.Pro654Leu	missense_variant	10/10	ENST00000467773.1
NOBOX	XM_017011742.3	c.1865C>T	p.Pro622Leu	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOBOX	ENST00000467773.1	c.1961C>T	p.Pro654Leu	missense_variant	10/10	5	NM_001080413.3
NOBOX	ENST00000483238.5	c.1865C>T	p.Pro622Leu	missense_variant	10/10	5		A2
NOBOX	ENST00000645489.1	c.1610C>T	p.Pro537Leu	missense_variant	8/8			P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384928 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 683394

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 21, 2024

The c.1961C>T (p.P654L) alteration is located in exon 10 (coding exon 10) of the NOBOX gene. This alteration results from a C to T substitution at nucleotide position 1961, causing the proline (P) at amino acid position 654 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.0015	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	14
Dann	Uncertain	0.98
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.20	T;T;T
MetaSVM	Uncertain	-0.082	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.34	T
Vest4		0.22, 0.18
MutPred		0.14		.;.;Loss of methylation at R653 (P = 0.1209);
MVP		0.71
MPC		0.10
ClinPred		0.97	D
GERP RS		2.5
Varity_R		0.051
gMVP		0.11

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

Publications

LitVar

Other links and lift over

dbSNP: rs1384557611; hg19: chr7-144094448;