chr7-144397625-C-T

Variant names:

• chr7-144397625-C-T
• rs75574842
• NM_001080413.3:c.1775-84G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001080413.3(NOBOX):​c.1775-84G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0149 in 1,210,516 control chromosomes in the GnomAD database, including 154 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (13 hom., cov: 32)
  • Exomes 𝑓: 0.015 (141 hom.)
• Consequence: NOBOX NM_001080413.3 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.487
• Publications: 2 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 (BayesDel_noAF=-0.95).
• BP6: Variant 7-144397625-C-T is Benign according to our data. Variant chr7-144397625-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1201840.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.011 (1673/152284) while in subpopulation NFE AF = 0.0168 (1145/68018). AF 95% confidence interval is 0.016. There are 13 homozygotes in GnomAd4. There are 788 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1673 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOBOX	NM_001080413.3	c.1775-84G>A		intron_variant	Intron 9 of 9	ENST00000467773.1	NP_001073882.3
NOBOX	NM_001436401.1	c.1424-84G>A		intron_variant	Intron 7 of 7		NP_001423330.1
NOBOX	NM_001436402.1	c.872-84G>A		intron_variant	Intron 6 of 6		NP_001423331.1
NOBOX	XM_017011742.3	c.1679-84G>A		intron_variant	Intron 9 of 9		XP_016867231.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOBOX	ENST00000467773.1	c.1775-84G>A		intron_variant	Intron 9 of 9	5	NM_001080413.3	ENSP00000419457.1
NOBOX	ENST00000483238.5	c.1679-84G>A		intron_variant	Intron 9 of 9	5		ENSP00000419565.1
NOBOX	ENST00000645489.1	c.1424-84G>A		intron_variant	Intron 7 of 7			ENSP00000496732.1
NOBOX	ENST00000643164.1	c.872-84G>A		intron_variant	Intron 6 of 6			ENSP00000495343.1

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1676 AN: 152166 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.00338

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.00681

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00601

Gnomad FIN AF: 0.0112

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0168

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.0154 AC: 16317 AN: 1058232 Hom.: 141 AF XY: 0.0150 AC XY: 7832 AN XY: 521720

African (AFR) AF: 0.00256 AC: 62 AN: 24198

American (AMR) AF: 0.00992 AC: 213 AN: 21482

Ashkenazi Jewish (ASJ) AF: 0.0221 AC: 391 AN: 17726

East Asian (EAS) AF: 0.0000591 AC: 2 AN: 33846

South Asian (SAS) AF: 0.00974 AC: 564 AN: 57896

European-Finnish (FIN) AF: 0.00851 AC: 260 AN: 30542

Middle Eastern (MID) AF: 0.0239 AC: 83 AN: 3476

European-Non Finnish (NFE) AF: 0.0171 AC: 14070 AN: 823164

Other (OTH) AF: 0.0146 AC: 672 AN: 45902

GnomAD4 genome AF: 0.0110 AC: 1673 AN: 152284 Hom.: 13 Cov.: 32 AF XY: 0.0106 AC XY: 788 AN XY: 74452

African (AFR) AF: 0.00337 AC: 140 AN: 41566

American (AMR) AF: 0.00680 AC: 104 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00601 AC: 29 AN: 4824

European-Finnish (FIN) AF: 0.0112 AC: 119 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0168 AC: 1145 AN: 68018

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.0117 Hom.: 5

Bravo AF: 0.0113

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 20, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.060
DANN	Benign	0.69
PhyloP100		-0.49
Mutation Taster		=100/0	polymorphism

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: rs75574842; hg19: chr7-144094718;