7-144397467-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001080413.3(NOBOX):c.1849C>T(p.His617Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00105 in 1,537,126 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.172

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018499076).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0011 (1522/1384820) while in subpopulation NFE AF= 0.00132 (1420/1078786). AF 95% confidence interval is 0.00126. There are 1 homozygotes in gnomad4_exome. There are 716 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 89 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOBOX	NM_001080413.3	c.1849C>T	p.His617Tyr	missense_variant	10/10	ENST00000467773.1
NOBOX	XM_017011742.3	c.1753C>T	p.His585Tyr	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOBOX	ENST00000467773.1	c.1849C>T	p.His617Tyr	missense_variant	10/10	5	NM_001080413.3
NOBOX	ENST00000483238.5	c.1753C>T	p.His585Tyr	missense_variant	10/10	5		A2
NOBOX	ENST00000645489.1	c.1498C>T	p.His500Tyr	missense_variant	8/8			P2
NOBOX	ENST00000643164.1			downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.000585 AC: 89 AN: 152188 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000546 AC: 76 AN: 139164 Hom.: 1 AF XY: 0.000522 AC XY: 39 AN XY: 74708

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.000554

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.000476

GnomAD4 exome AF: 0.00110 AC: 1522 AN: 1384820 Hom.: 1 Cov.: 31 AF XY: 0.00105 AC XY: 716 AN XY: 683342

Gnomad4 AFR exome AF: 0.000253

Gnomad4 AMR exome AF: 0.0000840

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.000914

Gnomad4 NFE exome AF: 0.00132

Gnomad4 OTH exome AF: 0.000950

GnomAD4 genome AF: 0.000584 AC: 89 AN: 152306 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74488

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000236 Hom.: 0

Bravo AF: 0.000499

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00126 AC: 4

ExAC AF: 0.000341 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Premature ovarian failure 5 Uncertain:1

Uncertain significance, 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, 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	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	2.6
Dann	Benign	0.73
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.78
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.58	T;T;T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.018	T;T;T
MetaSVM	Uncertain	-0.17	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.37	T
Vest4		0.18, 0.13
MVP		0.68
MPC		0.024
ClinPred		0.019	T
GERP RS		0.48
Varity_R		0.042
gMVP		0.16

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: rs139083352; hg19: chr7-144094560;