7-144410186-A-G

Variant names:

• chr7-144410186-A-G
• rs1208179
• NM_001080413.3:c.42T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001080413.3(NOBOX):​c.42T>C​(p.Gly14Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,569,332 control chromosomes in the GnomAD database, including 21,381 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1562 hom., cov: 33)
  • Exomes 𝑓: 0.16 (19819 hom.)
• Consequence: NOBOX NM_001080413.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.32
• Publications: 11 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 7-144410186-A-G is Benign according to our data. Variant chr7-144410186-A-G is described in ClinVar as Benign. ClinVar VariationId is 138536.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.215 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001080413.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOBOX	NM_001080413.3	MANE Select	c.42T>C	p.Gly14Gly	synonymous	Exon 1 of 10	NP_001073882.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOBOX	ENST00000467773.1	TSL:5 MANE Select	c.42T>C	p.Gly14Gly	synonymous	Exon 1 of 10	ENSP00000419457.1
	NOBOX	ENST00000483238.5	TSL:5	c.42T>C	p.Gly14Gly	synonymous	Exon 1 of 10	ENSP00000419565.1

Frequencies

GnomAD3 genomes AF: 0.129 AC: 19607 AN: 151878 Hom.: 1563 Cov.: 33

Gnomad AFR AF: 0.0611

Gnomad AMI AF: 0.264

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0114

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.190

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.114

GnomAD2 exomes AF: 0.147 AC: 27214 AN: 185426 AF XY: 0.154

Gnomad AFR exome AF: 0.0567

Gnomad AMR exome AF: 0.133

Gnomad ASJ exome AF: 0.113

Gnomad EAS exome AF: 0.00904

Gnomad FIN exome AF: 0.164

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.162 AC: 229509 AN: 1417336 Hom.: 19819 Cov.: 30 AF XY: 0.164 AC XY: 115188 AN XY: 700508

African (AFR) AF: 0.0591 AC: 1929 AN: 32644

American (AMR) AF: 0.128 AC: 4941 AN: 38472

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 2900 AN: 25368

East Asian (EAS) AF: 0.0104 AC: 396 AN: 37902

South Asian (SAS) AF: 0.224 AC: 17975 AN: 80370

European-Finnish (FIN) AF: 0.164 AC: 8290 AN: 50696

Middle Eastern (MID) AF: 0.168 AC: 959 AN: 5712

European-Non Finnish (NFE) AF: 0.169 AC: 183340 AN: 1087416

Other (OTH) AF: 0.149 AC: 8779 AN: 58756

GnomAD4 genome AF: 0.129 AC: 19622 AN: 151996 Hom.: 1562 Cov.: 33 AF XY: 0.130 AC XY: 9639 AN XY: 74270

African (AFR) AF: 0.0613 AC: 2540 AN: 41432

American (AMR) AF: 0.105 AC: 1611 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 372 AN: 3472

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5172

South Asian (SAS) AF: 0.226 AC: 1088 AN: 4814

European-Finnish (FIN) AF: 0.174 AC: 1832 AN: 10550

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11581 AN: 67970

Other (OTH) AF: 0.115 AC: 243 AN: 2112

Alfa AF: 0.149 Hom.: 1216

Bravo AF: 0.118

Asia WGS AF: 0.130 AC: 454 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Premature ovarian failure 5 Benign:2

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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 specified Benign:1

May 19, 2014

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.24
DANN	Benign	0.42
PhyloP100		-2.3
PromoterAI		0.030	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1208179; hg19: chr7-144107279; COSMIC: COSV71989190;