7-144397490-G-A

Position:

• chr7-144397490-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001080413.3(NOBOX):​c.1826C>T​(p.Pro609Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000514 in 1,536,732 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (4 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 4.17

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010829002).
• BP6: Variant 7-144397490-G-A is Benign according to our data. Variant chr7-144397490-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 791163.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00135 (205/152328) while in subpopulation AFR AF= 0.00397 (165/41570). AF 95% confidence interval is 0.00347. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 205 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOBOX	NM_001080413.3	c.1826C>T	p.Pro609Leu	missense_variant	10/10	ENST00000467773.1	NP_001073882.3
NOBOX	XM_017011742.3	c.1730C>T	p.Pro577Leu	missense_variant	10/10		XP_016867231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOBOX	ENST00000467773.1	c.1826C>T	p.Pro609Leu	missense_variant	10/10	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5	c.1730C>T	p.Pro577Leu	missense_variant	10/10	5		ENSP00000419565.1
NOBOX	ENST00000645489.1	c.1475C>T	p.Pro492Leu	missense_variant	8/8			ENSP00000496732.1
NOBOX	ENST00000643164.1	c.*21C>T		downstream_gene_variant				ENSP00000495343.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152210 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00398

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000850 AC: 118 AN: 138742 Hom.: 0 AF XY: 0.000872 AC XY: 65 AN XY: 74530

Gnomad AFR exome AF: 0.00403

Gnomad AMR exome AF: 0.000448

Gnomad ASJ exome AF: 0.000599

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00220

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000270

Gnomad OTH exome AF: 0.00167

GnomAD4 exome AF: 0.000423 AC: 585 AN: 1384404 Hom.: 4 Cov.: 31 AF XY: 0.000492 AC XY: 336 AN XY: 683064

Gnomad4 AFR exome AF: 0.00408

Gnomad4 AMR exome AF: 0.000421

Gnomad4 ASJ exome AF: 0.000676

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00221

Gnomad4 FIN exome AF: 0.0000286

Gnomad4 NFE exome AF: 0.000182

Gnomad4 OTH exome AF: 0.000622

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152328 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74484

Gnomad4 AFR AF: 0.00397

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000426 Hom.: 0

Bravo AF: 0.00145

ESP6500AA AF: 0.00361 AC: 5

ESP6500EA AF: 0.000629 AC: 2

ExAC AF: 0.00124 AC: 29

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2024	Reported as one of many candidate variants in a 46,XX male patient with inguinal testes, micropenis and hypospadias (Knarston K. 2018 https://minerva-access.unimelb.edu.au/handle/11343/221695); variant maternally inherited; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: Knarston2018[Thesis]) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 24, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 09, 2024

The c.1826C>T (p.P609L) alteration is located in exon 10 (coding exon 10) of the NOBOX gene. This alteration results from a C to T substitution at nucleotide position 1826, causing the proline (P) at amino acid position 609 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Premature ovarian failure 5 Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	.;.;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.70	T;T;T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Uncertain	0.10	D
MutationAssessor	Benign	1.5	.;.;L
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-2.6	.;D;D
REVEL	Benign	0.26
Sift	Uncertain	0.0010	.;D;D
Sift4G	Uncertain	0.015	.;D;D
Vest4		0.23, 0.17
MVP		0.82
MPC		0.14
ClinPred		0.038	T
GERP RS		3.6
Varity_R		0.043
gMVP		0.13

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: rs115882574; hg19: chr7-144094583;