rs727714

Positions:

• chr7-144401899-G-A
• chr7-144401899-G-C
• chr7-144401899-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001080413.3(NOBOX):​c.262C>T​(p.Leu88Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 1,609,278 control chromosomes in the GnomAD database, including 290,889 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.61 (28882 hom., cov: 31)
  • Exomes 𝑓: 0.59 (262007 hom.)
• Consequence: NOBOX NM_001080413.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.146

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-144401899-G-A is Benign according to our data. Variant chr7-144401899-G-A is described in ClinVar as [Benign]. Clinvar id is 359152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-144401899-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.146 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.811 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOBOX	NM_001080413.3	c.262C>T	p.Leu88Leu	synonymous_variant	3/10	ENST00000467773.1	NP_001073882.3
NOBOX	XM_017011742.3	c.262C>T	p.Leu88Leu	synonymous_variant	3/10		XP_016867231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOBOX	ENST00000467773.1	c.262C>T	p.Leu88Leu	synonymous_variant	3/10	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5	c.262C>T	p.Leu88Leu	synonymous_variant	3/10	5		ENSP00000419565.1
NOBOX	ENST00000645489.1	c.38-302C>T		intron_variant				ENSP00000496732.1
NOBOX	ENST00000643164.1	c.38-1587C>T		intron_variant				ENSP00000495343.1

Frequencies

GnomAD3 genomes AF: 0.612 AC: 92907 AN: 151814 Hom.: 28852 Cov.: 31

Gnomad AFR AF: 0.645

Gnomad AMI AF: 0.656

Gnomad AMR AF: 0.620

Gnomad ASJ AF: 0.606

Gnomad EAS AF: 0.829

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.569

Gnomad OTH AF: 0.619

GnomAD3 exomes AF: 0.632 AC: 157122 AN: 248510 Hom.: 51038 AF XY: 0.638 AC XY: 86104 AN XY: 134882

Gnomad AFR exome AF: 0.651

Gnomad AMR exome AF: 0.651

Gnomad ASJ exome AF: 0.599

Gnomad EAS exome AF: 0.822

Gnomad SAS exome AF: 0.803

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.571

Gnomad OTH exome AF: 0.598

GnomAD4 exome AF: 0.595 AC: 866739 AN: 1457346 Hom.: 262007 Cov.: 33 AF XY: 0.602 AC XY: 436375 AN XY: 725156

Gnomad4 AFR exome AF: 0.646

Gnomad4 AMR exome AF: 0.646

Gnomad4 ASJ exome AF: 0.603

Gnomad4 EAS exome AF: 0.788

Gnomad4 SAS exome AF: 0.799

Gnomad4 FIN exome AF: 0.529

Gnomad4 NFE exome AF: 0.570

Gnomad4 OTH exome AF: 0.616

GnomAD4 genome AF: 0.612 AC: 92989 AN: 151932 Hom.: 28882 Cov.: 31 AF XY: 0.617 AC XY: 45817 AN XY: 74246

Gnomad4 AFR AF: 0.644

Gnomad4 AMR AF: 0.620

Gnomad4 ASJ AF: 0.606

Gnomad4 EAS AF: 0.829

Gnomad4 SAS AF: 0.832

Gnomad4 FIN AF: 0.538

Gnomad4 NFE AF: 0.569

Gnomad4 OTH AF: 0.624

Alfa AF: 0.578 Hom.: 31227

Bravo AF: 0.615

Asia WGS AF: 0.812 AC: 2821 AN: 3478

EpiCase AF: 0.583

EpiControl AF: 0.586

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	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
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
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.4
DANN	Benign	0.53

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: rs727714; hg19: chr7-144098992; COSMIC: COSV56196559;