chr7-144397486-G-C

Variant names:

• chr7-144397486-G-C
• rs2053901501
• NM_001080413.3:c.1830C>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001080413.3(NOBOX):​c.1830C>G​(p.Phe610Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000144 in 1,384,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84
• Publications: 0 publications found

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]

NOBOX Gene-Disease associations (from GenCC):

• premature ovarian failure 5

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2687386).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOBOX	NM_001080413.3	c.1830C>G	p.Phe610Leu	missense_variant	Exon 10 of 10	ENST00000467773.1	NP_001073882.3
NOBOX	NM_001436401.1	c.1479C>G	p.Phe493Leu	missense_variant	Exon 8 of 8		NP_001423330.1
NOBOX	NM_001436402.1	c.927C>G	p.Phe309Leu	missense_variant	Exon 7 of 7		NP_001423331.1
NOBOX	XM_017011742.3	c.1734C>G	p.Phe578Leu	missense_variant	Exon 10 of 10		XP_016867231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOBOX	ENST00000467773.1	c.1830C>G	p.Phe610Leu	missense_variant	Exon 10 of 10	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5	c.1734C>G	p.Phe578Leu	missense_variant	Exon 10 of 10	5		ENSP00000419565.1
NOBOX	ENST00000645489.1	c.1479C>G	p.Phe493Leu	missense_variant	Exon 8 of 8			ENSP00000496732.1
NOBOX	ENST00000643164.1	c.*25C>G		downstream_gene_variant				ENSP00000495343.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000144 AC: 2 AN: 1384760 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 683300

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25164

East Asian (EAS) AF: 0.00 AC: 0 AN: 35732

South Asian (SAS) AF: 0.00 AC: 0 AN: 79226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1078766

Other (OTH) AF: 0.00 AC: 0 AN: 57910

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Premature ovarian failure 5 Uncertain:1

Jan 15, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	.;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.27	T;T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.5	.;.;L
PhyloP100		1.8
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-2.2	.;N;N
REVEL	Benign	0.21
Sift	Benign	0.13	.;T;T
Sift4G	Benign	0.58	.;T;T
Vest4		0.20, 0.39
MutPred		0.24		.;.;Gain of stability (P = 0.3015);
MVP		0.83
MPC		0.027
ClinPred		0.16	T
GERP RS		2.5
Varity_R		0.12
gMVP		0.12
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs2053901501; hg19: chr7-144094579;