7-144397520-G-T

Position:

• chr7-144397520-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080413.3(NOBOX):​c.1796C>A​(p.Pro599His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,533,932 control chromosomes in the GnomAD database, including 21,039 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1556 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19483 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.420

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007170588).
• BP6: Variant 7-144397520-G-T is Benign according to our data. Variant chr7-144397520-G-T is described in ClinVar as [Benign]. Clinvar id is 359135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOBOX	NM_001080413.3	c.1796C>A	p.Pro599His	missense_variant	10/10	ENST00000467773.1	NP_001073882.3
NOBOX	XM_017011742.3	c.1700C>A	p.Pro567His	missense_variant	10/10		XP_016867231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOBOX	ENST00000467773.1	c.1796C>A	p.Pro599His	missense_variant	10/10	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5	c.1700C>A	p.Pro567His	missense_variant	10/10	5		ENSP00000419565.1
NOBOX	ENST00000645489.1	c.1445C>A	p.Pro482His	missense_variant	8/8			ENSP00000496732.1
NOBOX	ENST00000643164.1	c.893C>A	p.Pro298His	missense_variant	7/7			ENSP00000495343.1

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19253 AN: 152060 Hom.: 1557 Cov.: 32

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.113

GnomAD3 exomes AF: 0.148 AC: 20191 AN: 136464 Hom.: 1761 AF XY: 0.156 AC XY: 11482 AN XY: 73380

Gnomad AFR exome AF: 0.0485

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00888

Gnomad SAS exome AF: 0.226

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.162 AC: 223988 AN: 1381754 Hom.: 19483 Cov.: 33 AF XY: 0.165 AC XY: 112228 AN XY: 681460

Gnomad4 AFR exome AF: 0.0479

Gnomad4 AMR exome AF: 0.130

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.0109

Gnomad4 SAS exome AF: 0.225

Gnomad4 FIN exome AF: 0.152

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.127 AC: 19263 AN: 152178 Hom.: 1556 Cov.: 32 AF XY: 0.127 AC XY: 9415 AN XY: 74402

Gnomad4 AFR AF: 0.0521

Gnomad4 AMR AF: 0.108

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0112

Gnomad4 SAS AF: 0.227

Gnomad4 FIN AF: 0.159

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.115

Alfa AF: 0.156 Hom.: 2369

Bravo AF: 0.117

TwinsUK AF: 0.163 AC: 604

ALSPAC AF: 0.162 AC: 624

ExAC AF: 0.144 AC: 3274

Asia WGS AF: 0.127 AC: 444 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Premature ovarian failure 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.83
DEOGEN2	Benign	0.13	.;.;T;.
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.52	T;T;T;T
MetaRNN	Benign	0.0072	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;.;L;.
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.1	.;D;D;.
REVEL	Benign	0.017
Sift	Benign	0.18	.;T;T;.
Sift4G	Benign	0.32	.;T;T;.
Vest4		0.091, 0.28
MPC		0.041
ClinPred		0.0081	T
GERP RS		1.4
Varity_R		0.075
gMVP		0.15

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: rs1208216; hg19: chr7-144094613;