7-144397378-T-C

Variant names:

• chr7-144397378-T-C
• rs116937127
• NM_001080413.3:c.1938A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP7 BS2

The NM_001080413.3(NOBOX):​c.1938A>G​(p.Ser646Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,536,720 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: NOBOX NM_001080413.3 synonymous
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.162
• 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP7: Synonymous conserved (PhyloP=-0.162 with no splicing effect.
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOBOX	NM_001080413.3	c.1938A>G	p.Ser646Ser	synonymous_variant	Exon 10 of 10	ENST00000467773.1	NP_001073882.3
NOBOX	NM_001436401.1	c.1587A>G	p.Ser529Ser	synonymous_variant	Exon 8 of 8		NP_001423330.1
NOBOX	NM_001436402.1	c.1035A>G	p.Ser345Ser	synonymous_variant	Exon 7 of 7		NP_001423331.1
NOBOX	XM_017011742.3	c.1842A>G	p.Ser614Ser	synonymous_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.1938A>G	p.Ser646Ser	synonymous_variant	Exon 10 of 10	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5	c.1842A>G	p.Ser614Ser	synonymous_variant	Exon 10 of 10	5		ENSP00000419565.1
NOBOX	ENST00000645489.1	c.1587A>G	p.Ser529Ser	synonymous_variant	Exon 8 of 8			ENSP00000496732.1
NOBOX	ENST00000643164.1	c.*133A>G		downstream_gene_variant				ENSP00000495343.1

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.000118

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.0000637 AC: 9 AN: 141288 AF XY: 0.0000793

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000530

Gnomad OTH exome AF: 0.000470

GnomAD4 exome AF: 0.000127 AC: 176 AN: 1384476 Hom.: 0 Cov.: 31 AF XY: 0.000130 AC XY: 89 AN XY: 683212

African (AFR) AF: 0.00 AC: 0 AN: 31578

American (AMR) AF: 0.000392 AC: 14 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 79228

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34998

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.000144 AC: 155 AN: 1078468

Other (OTH) AF: 0.000121 AC: 7 AN: 57904

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152244 Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6 AN XY: 74422

African (AFR) AF: 0.00 AC: 0 AN: 41550

American (AMR) AF: 0.0000653 AC: 1 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68008

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Premature ovarian failure 5 Uncertain:1

Jan 13, 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
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.2
DANN	Benign	0.52
PhyloP100		-0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs116937127; hg19: chr7-144094471;