rs2699503

Variant names:

• chr7-144398507-A-G
• rs2699503
• NM_001080413.3:c.1549T>C

Your query was ambiguous. Multiple possible variants found:

• chr7-144398507-A-G
• chr7-144398507-A-C
• chr7-144398507-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001080413.3(NOBOX):​c.1549T>C​(p.Phe517Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.575 in 1,535,894 control chromosomes in the GnomAD database, including 258,161 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (27119 hom., cov: 30)
  • Exomes 𝑓: 0.57 (231042 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.77
• Publications: 27 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.9674754E-6).
• BP6: Variant 7-144398507-A-G is Benign according to our data. Variant chr7-144398507-A-G is described in ClinVar as Benign. ClinVar VariationId is 286525.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.81 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOBOX	NM_001080413.3	MANE Select	c.1549T>C	p.Phe517Leu	missense	Exon 9 of 10	NP_001073882.3	O60393-1
	NOBOX	NM_001436401.1		c.1198T>C	p.Phe400Leu	missense	Exon 7 of 8	NP_001423330.1	A0A2R8Y8C8
	NOBOX	NM_001436402.1		c.646T>C	p.Phe216Leu	missense	Exon 6 of 7	NP_001423331.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOBOX	ENST00000467773.1	TSL:5 MANE Select	c.1549T>C	p.Phe517Leu	missense	Exon 9 of 10	ENSP00000419457.1	O60393-1
	NOBOX	ENST00000645489.2		c.1198T>C	p.Phe400Leu	missense	Exon 7 of 8	ENSP00000496732.1
	NOBOX	ENST00000643164.2		c.646T>C	p.Phe216Leu	missense	Exon 6 of 7	ENSP00000495343.2

Frequencies

GnomAD3 genomes AF: 0.593 AC: 89838 AN: 151604 Hom.: 27090 Cov.: 30

Gnomad AFR AF: 0.627

Gnomad AMI AF: 0.650

Gnomad AMR AF: 0.607

Gnomad ASJ AF: 0.586

Gnomad EAS AF: 0.829

Gnomad SAS AF: 0.831

Gnomad FIN AF: 0.512

Gnomad MID AF: 0.706

Gnomad NFE AF: 0.545

Gnomad OTH AF: 0.607

GnomAD2 exomes AF: 0.634 AC: 88686 AN: 139948 AF XY: 0.644

Gnomad AFR exome AF: 0.636

Gnomad AMR exome AF: 0.639

Gnomad ASJ exome AF: 0.580

Gnomad EAS exome AF: 0.822

Gnomad FIN exome AF: 0.505

Gnomad NFE exome AF: 0.553

Gnomad OTH exome AF: 0.591

GnomAD4 exome AF: 0.573 AC: 792533 AN: 1384172 Hom.: 231042 Cov.: 44 AF XY: 0.580 AC XY: 396440 AN XY: 683020

African (AFR) AF: 0.630 AC: 19900 AN: 31576

American (AMR) AF: 0.633 AC: 22582 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.582 AC: 14656 AN: 25178

East Asian (EAS) AF: 0.786 AC: 28088 AN: 35732

South Asian (SAS) AF: 0.797 AC: 63128 AN: 79214

European-Finnish (FIN) AF: 0.501 AC: 17549 AN: 35000

Middle Eastern (MID) AF: 0.663 AC: 3667 AN: 5532

European-Non Finnish (NFE) AF: 0.546 AC: 588308 AN: 1078362

Other (OTH) AF: 0.599 AC: 34655 AN: 57882

GnomAD4 genome AF: 0.593 AC: 89915 AN: 151722 Hom.: 27119 Cov.: 30 AF XY: 0.598 AC XY: 44319 AN XY: 74130

African (AFR) AF: 0.627 AC: 25924 AN: 41336

American (AMR) AF: 0.607 AC: 9262 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.586 AC: 2031 AN: 3468

East Asian (EAS) AF: 0.829 AC: 4236 AN: 5112

South Asian (SAS) AF: 0.832 AC: 3997 AN: 4804

European-Finnish (FIN) AF: 0.512 AC: 5401 AN: 10554

Middle Eastern (MID) AF: 0.707 AC: 208 AN: 294

European-Non Finnish (NFE) AF: 0.545 AC: 36975 AN: 67874

Other (OTH) AF: 0.612 AC: 1291 AN: 2110

Alfa AF: 0.575 Hom.: 29775

Bravo AF: 0.596

TwinsUK AF: 0.557 AC: 2067

ALSPAC AF: 0.526 AC: 2027

ExAC AF: 0.554 AC: 16006

Asia WGS AF: 0.809 AC: 2812 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Premature ovarian failure 5 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0000050	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M
PhyloP100		1.8
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.022
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.13	T
Vest4		0.068
MutPred		0.26		Gain of phosphorylation at S520 (P = 0.1252)
MPC		0.096
ClinPred		0.030	T
GERP RS		3.0
Varity_R		0.18
gMVP		0.21
Mutation Taster		=97/3	polymorphism (auto)

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: rs2699503; hg19: chr7-144095600; COSMIC: COSV56196421;