7-144397549-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080413.3(NOBOX):c.1775-8C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,509,682 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00063 (10 hom.)
• Consequence: NOBOX NM_001080413.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.001858
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0610

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 7-144397549-G-T is Benign according to our data. Variant chr7-144397549-G-T is described in ClinVar as [Benign]. Clinvar id is 716086.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00635 (968/152358) while in subpopulation AFR AF= 0.022 (914/41596). AF 95% confidence interval is 0.0208. There are 10 homozygotes in gnomad4. There are 458 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 966 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOBOX	NM_001080413.3	c.1775-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000467773.1
NOBOX	XM_017011742.3	c.1679-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOBOX	ENST00000467773.1	c.1775-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001080413.3
NOBOX	ENST00000483238.5	c.1679-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A2
NOBOX	ENST00000643164.1	c.872-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
NOBOX	ENST00000645489.1	c.1424-8C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				P2

Frequencies

GnomAD3 genomes AF: 0.00635 AC: 966 AN: 152240 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00161 AC: 191 AN: 118784 Hom.: 2 AF XY: 0.00129 AC XY: 82 AN XY: 63742

Gnomad AFR exome AF: 0.0240

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000630

Gnomad OTH exome AF: 0.000284

GnomAD4 exome AF: 0.000626 AC: 850 AN: 1357324 Hom.: 10 Cov.: 31 AF XY: 0.000528 AC XY: 352 AN XY: 666336

Gnomad4 AFR exome AF: 0.0231

Gnomad4 AMR exome AF: 0.00107

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000662

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000150

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00635 AC: 968 AN: 152358 Hom.: 10 Cov.: 32 AF XY: 0.00615 AC XY: 458 AN XY: 74498

Gnomad4 AFR AF: 0.0220

Gnomad4 AMR AF: 0.00235

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00663

Alfa AF: 0.00312 Hom.: 0

Bravo AF: 0.00706

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Premature ovarian failure 5 Benign:1

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 provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	1.0
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0019
dbscSNV1_RF	Benign	0.046
SpliceAI score (max)		0.11		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: rs149880524; hg19: chr7-144094642;