chr7-144397325-T-C

Variant names:

• chr7-144397325-T-C
• rs77802098
• NM_001080413.3:c.1991A>G

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.1991A>G​(p.Lys664Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0386 in 1,537,224 control chromosomes in the GnomAD database, including 1,291 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.030 (79 hom., cov: 32)
  • Exomes 𝑓: 0.040 (1212 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.875
• Publications: 7 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=0.0027282238).
• BP6: Variant 7-144397325-T-C is Benign according to our data. Variant chr7-144397325-T-C is described in ClinVar as Benign. ClinVar VariationId is 359131.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0607 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.1991A>G	p.Lys664Arg	missense	Exon 10 of 10	NP_001073882.3	O60393-1
	NOBOX	NM_001436401.1		c.1640A>G	p.Lys547Arg	missense	Exon 8 of 8	NP_001423330.1	A0A2R8Y8C8
	NOBOX	NM_001436402.1		c.1088A>G	p.Lys363Arg	missense	Exon 7 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.1991A>G	p.Lys664Arg	missense	Exon 10 of 10	ENSP00000419457.1	O60393-1
	NOBOX	ENST00000645489.2		c.1640A>G	p.Lys547Arg	missense	Exon 8 of 8	ENSP00000496732.1
	NOBOX	ENST00000643164.2		c.1088A>G	p.Lys363Arg	missense	Exon 7 of 7	ENSP00000495343.2

Frequencies

GnomAD3 genomes AF: 0.0301 AC: 4575 AN: 152174 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0524

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0104

Gnomad FIN AF: 0.0441

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0425

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0304 AC: 4307 AN: 141844 AF XY: 0.0298

Gnomad AFR exome AF: 0.00763

Gnomad AMR exome AF: 0.0243

Gnomad ASJ exome AF: 0.0528

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0439

Gnomad OTH exome AF: 0.0404

GnomAD4 exome AF: 0.0395 AC: 54725 AN: 1384932 Hom.: 1212 Cov.: 32 AF XY: 0.0393 AC XY: 26867 AN XY: 683396

African (AFR) AF: 0.00684 AC: 216 AN: 31594

American (AMR) AF: 0.0266 AC: 950 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 1407 AN: 25182

East Asian (EAS) AF: 0.0000840 AC: 3 AN: 35734

South Asian (SAS) AF: 0.0125 AC: 992 AN: 79236

European-Finnish (FIN) AF: 0.0453 AC: 1584 AN: 35000

Middle Eastern (MID) AF: 0.0662 AC: 377 AN: 5696

European-Non Finnish (NFE) AF: 0.0435 AC: 46944 AN: 1078878

Other (OTH) AF: 0.0389 AC: 2252 AN: 57916

GnomAD4 genome AF: 0.0300 AC: 4572 AN: 152292 Hom.: 79 Cov.: 32 AF XY: 0.0301 AC XY: 2244 AN XY: 74474

African (AFR) AF: 0.00847 AC: 352 AN: 41560

American (AMR) AF: 0.0332 AC: 508 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0524 AC: 182 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0102 AC: 49 AN: 4826

European-Finnish (FIN) AF: 0.0441 AC: 468 AN: 10620

Middle Eastern (MID) AF: 0.0646 AC: 19 AN: 294

European-Non Finnish (NFE) AF: 0.0425 AC: 2889 AN: 68014

Other (OTH) AF: 0.0440 AC: 93 AN: 2114

Alfa AF: 0.0391 Hom.: 255

Bravo AF: 0.0294

TwinsUK AF: 0.0456 AC: 169

ALSPAC AF: 0.0418 AC: 161

ESP6500AA AF: 0.00795 AC: 11

ESP6500EA AF: 0.0475 AC: 151

ExAC AF: 0.0235 AC: 567

Asia WGS AF: 0.00693 AC: 25 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.19
DANN	Benign	0.71
DEOGEN2	Benign	0.033	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0097	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.88
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.30	N
REVEL	Benign	0.11
Sift	Benign	0.066	T
Sift4G	Benign	0.26	T
Vest4		0.027
MPC		0.021
ClinPred		0.0077	T
GERP RS		-7.2
Varity_R		0.025
gMVP		0.052
Mutation Taster		=100/0	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: rs77802098; hg19: chr7-144094418; COSMIC: COSV107299482; COSMIC: COSV107299482;