chr7-144397520-G-T

Variant names:

• chr7-144397520-G-T
• rs1208216
• NM_001080413.3:c.1796C>A

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.1796C>A​(p.Pro599His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,533,932 control chromosomes in the GnomAD database, including 21,039 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1556 hom., cov: 32)
  • Exomes 𝑓: 0.16 (19483 hom.)
• Consequence: NOBOX NM_001080413.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.420
• 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=0.007170588).
• BP6: Variant 7-144397520-G-T is Benign according to our data. Variant chr7-144397520-G-T is described in ClinVar as Benign. ClinVar VariationId is 359135.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.216 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.1796C>A	p.Pro599His	missense	Exon 10 of 10	NP_001073882.3	O60393-1
	NOBOX	NM_001436401.1		c.1445C>A	p.Pro482His	missense	Exon 8 of 8	NP_001423330.1	A0A2R8Y8C8
	NOBOX	NM_001436402.1		c.893C>A	p.Pro298His	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.1796C>A	p.Pro599His	missense	Exon 10 of 10	ENSP00000419457.1	O60393-1
	NOBOX	ENST00000645489.2		c.1445C>A	p.Pro482His	missense	Exon 8 of 8	ENSP00000496732.1
	NOBOX	ENST00000643164.2		c.893C>A	p.Pro298His	missense	Exon 7 of 7	ENSP00000495343.2

Frequencies

GnomAD3 genomes AF: 0.127 AC: 19253 AN: 152060 Hom.: 1557 Cov.: 32

Gnomad AFR AF: 0.0521

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.107

Gnomad EAS AF: 0.0112

Gnomad SAS AF: 0.227

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.170

Gnomad OTH AF: 0.113

GnomAD2 exomes AF: 0.148 AC: 20191 AN: 136464 AF XY: 0.156

Gnomad AFR exome AF: 0.0485

Gnomad AMR exome AF: 0.136

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.00888

Gnomad FIN exome AF: 0.152

Gnomad NFE exome AF: 0.167

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.162 AC: 223988 AN: 1381754 Hom.: 19483 Cov.: 33 AF XY: 0.165 AC XY: 112228 AN XY: 681460

African (AFR) AF: 0.0479 AC: 1509 AN: 31508

American (AMR) AF: 0.130 AC: 4615 AN: 35526

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 2772 AN: 24960

East Asian (EAS) AF: 0.0109 AC: 388 AN: 35690

South Asian (SAS) AF: 0.225 AC: 17738 AN: 78934

European-Finnish (FIN) AF: 0.152 AC: 5303 AN: 34916

Middle Eastern (MID) AF: 0.172 AC: 973 AN: 5666

European-Non Finnish (NFE) AF: 0.169 AC: 182075 AN: 1076796

Other (OTH) AF: 0.149 AC: 8615 AN: 57758

GnomAD4 genome AF: 0.127 AC: 19263 AN: 152178 Hom.: 1556 Cov.: 32 AF XY: 0.127 AC XY: 9415 AN XY: 74402

African (AFR) AF: 0.0521 AC: 2165 AN: 41530

American (AMR) AF: 0.108 AC: 1655 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.107 AC: 371 AN: 3468

East Asian (EAS) AF: 0.0112 AC: 58 AN: 5166

South Asian (SAS) AF: 0.227 AC: 1093 AN: 4820

European-Finnish (FIN) AF: 0.159 AC: 1684 AN: 10606

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.170 AC: 11566 AN: 67972

Other (OTH) AF: 0.115 AC: 242 AN: 2112

Alfa AF: 0.153 Hom.: 5205

Bravo AF: 0.117

TwinsUK AF: 0.163 AC: 604

ALSPAC AF: 0.162 AC: 624

ExAC AF: 0.144 AC: 3274

Asia WGS AF: 0.127 AC: 444 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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.83
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.42
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.017
Sift	Benign	0.18	T
Sift4G	Benign	0.32	T
Vest4		0.091
MPC		0.041
ClinPred		0.0081	T
GERP RS		1.4
Varity_R		0.075
gMVP		0.15
Mutation Taster		=99/1	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: rs1208216; hg19: chr7-144094613; COSMIC: COSV107299451;