7-144410186-A-G

Position:

• chr7-144410186-A-G

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.42T>C​(p.Gly14Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,569,332 control chromosomes in the GnomAD database, including 21,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1562 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19819 hom.)
• Consequence: NOBOX NM_001080413.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.32

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=-0.93).
• BP6: Variant 7-144410186-A-G is Benign according to our data. Variant chr7-144410186-A-G is described in ClinVar as [Benign]. Clinvar id is 138536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOBOX	NM_001080413.3	c.42T>C	p.Gly14Gly	synonymous_variant	1/10	ENST00000467773.1	NP_001073882.3
NOBOX	XM_017011742.3	c.42T>C	p.Gly14Gly	synonymous_variant	1/10		XP_016867231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOBOX	ENST00000467773.1	c.42T>C	p.Gly14Gly	synonymous_variant	1/10	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5	c.42T>C	p.Gly14Gly	synonymous_variant	1/10	5		ENSP00000419565.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19607 AN: 151878 Hom.: 1563 Cov.: 33

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.114

GnomAD3 exomes AF: 0.147 AC: 27214 AN: 185426 Hom.: 2292 AF XY: 0.154 AC XY: 15148 AN XY: 98370

Gnomad AFR exome AF: 0.0567

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.00904

Gnomad SAS exome AF: 0.224

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.162 AC: 229509 AN: 1417336 Hom.: 19819 Cov.: 30 AF XY: 0.164 AC XY: 115188 AN XY: 700508

Gnomad4 AFR exome AF: 0.0591

Gnomad4 AMR exome AF: 0.128

Gnomad4 ASJ exome AF: 0.114

Gnomad4 EAS exome AF: 0.0104

Gnomad4 SAS exome AF: 0.224

Gnomad4 FIN exome AF: 0.164

Gnomad4 NFE exome AF: 0.169

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.129 AC: 19622 AN: 151996 Hom.: 1562 Cov.: 33 AF XY: 0.130 AC XY: 9639 AN XY: 74270

Gnomad4 AFR AF: 0.0613

Gnomad4 AMR AF: 0.105

Gnomad4 ASJ AF: 0.107

Gnomad4 EAS AF: 0.0114

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.174

Gnomad4 NFE AF: 0.170

Gnomad4 OTH AF: 0.115

Alfa AF: 0.152 Hom.: 1085

Bravo AF: 0.118

Asia WGS AF: 0.130 AC: 454 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	Genome-Nilou Lab	Sep 05, 2021	- -
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

May 19, 2014

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. -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.24
DANN	Benign	0.42

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: rs1208179; hg19: chr7-144107279; COSMIC: COSV71989190;