7-144397415-G-A

Position:

• chr7-144397415-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001080413.3(NOBOX):​c.1901C>T​(p.Pro634Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000505 in 1,384,938 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/20 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: 0.0000051 (0 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.717

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_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07623121).
• BS2: High AC in GnomAdExome4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOBOX	NM_001080413.3	c.1901C>T	p.Pro634Leu	missense_variant	10/10	ENST00000467773.1	NP_001073882.3
NOBOX	XM_017011742.3	c.1805C>T	p.Pro602Leu	missense_variant	10/10		XP_016867231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOBOX	ENST00000467773.1	c.1901C>T	p.Pro634Leu	missense_variant	10/10	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5	c.1805C>T	p.Pro602Leu	missense_variant	10/10	5		ENSP00000419565.1
NOBOX	ENST00000645489.1	c.1550C>T	p.Pro517Leu	missense_variant	8/8			ENSP00000496732.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000505 AC: 7 AN: 1384938 Hom.: 0 Cov.: 31 AF XY: 0.00000439 AC XY: 3 AN XY: 683400

Gnomad4 AFR exome AF: 0.0000950

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: 9.27e-7

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jul 01, 2023

NOBOX: PM2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.075	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	13
DANN	Benign	0.92
DEOGEN2	Benign	0.041	.;.;T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.079	D
MetaRNN	Benign	0.076	T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.0	.;.;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.060	.;N;N
REVEL	Benign	0.14
Sift	Benign	0.047	.;D;T
Sift4G	Benign	0.088	.;T;T
Vest4		0.093, 0.080
MutPred		0.20		.;.;Loss of glycosylation at T631 (P = 0.0964);
MVP		0.63
MPC		0.023
ClinPred		0.080	T
GERP RS		2.6
Varity_R		0.028
gMVP		0.11

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1213668924; hg19: chr7-144094508; COSMIC: COSV104551257; COSMIC: COSV104551257;