7-144397325-T-C

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.1991A>G(p.Lys664Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,537,224 control chromosomes in the GnomAD database, including 1,291 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (79 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1212 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.875

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=0.0027282238).
• BP6: Variant 7-144397325-T-C is Benign according to our data. Variant chr7-144397325-T-C is described in ClinVar as [Benign]. Clinvar id is 359131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0607 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOBOX	NM_001080413.3	c.1991A>G	p.Lys664Arg	missense_variant	10/10	ENST00000467773.1
NOBOX	XM_017011742.3	c.1895A>G	p.Lys632Arg	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOBOX	ENST00000467773.1	c.1991A>G	p.Lys664Arg	missense_variant	10/10	5	NM_001080413.3
NOBOX	ENST00000483238.5	c.1895A>G	p.Lys632Arg	missense_variant	10/10	5		A2
NOBOX	ENST00000645489.1	c.1640A>G	p.Lys547Arg	missense_variant	8/8			P2

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4575 AN: 152174 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0425

Gnomad OTH AF: 0.0445

GnomAD3 exomes AF: 0.0304 AC: 4307 AN: 141844 Hom.: 98 AF XY: 0.0298 AC XY: 2260 AN XY: 75954

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0528

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0113

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0404

GnomAD4 exome AF: 0.0395 AC: 54725 AN: 1384932 Hom.: 1212 Cov.: 32 AF XY: 0.0393 AC XY: 26867 AN XY: 683396

Gnomad4 AFR exome AF: 0.00684

Gnomad4 AMR exome AF: 0.0266

Gnomad4 ASJ exome AF: 0.0559

Gnomad4 EAS exome AF: 0.0000840

Gnomad4 SAS exome AF: 0.0125

Gnomad4 FIN exome AF: 0.0453

Gnomad4 NFE exome AF: 0.0435

Gnomad4 OTH exome AF: 0.0389

GnomAD4 genome AF: 0.0300 AC: 4572 AN: 152292 Hom.: 79 Cov.: 32 AF XY: 0.0301 AC XY: 2244 AN XY: 74474

Gnomad4 AFR AF: 0.00847

Gnomad4 AMR AF: 0.0332

Gnomad4 ASJ AF: 0.0524

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.0441

Gnomad4 NFE AF: 0.0425

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0420 Hom.: 184

Bravo AF: 0.0294

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0418 AC: 161

ESP6500AA AF: 0.00795 AC: 11

ESP6500EA AF: 0.0475 AC: 151

ExAC AF: 0.0235 AC: 567

Asia WGS AF: 0.00693 AC: 25 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Premature ovarian failure 5 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 12, 2016

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	0.19
Dann	Benign	0.71
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.51	T;T;T
MetaRNN	Benign	0.0027	T;T;T
MetaSVM	Benign	-0.48	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
Vest4		0.027, 0.043
MPC		0.021
ClinPred		0.0077	T
GERP RS		-7.2
Varity_R		0.025
gMVP		0.052

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: rs77802098; hg19: chr7-144094418;