chr8-89935309-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002485.5(NBN):c.*273G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 381,352 control chromosomes in the GnomAD database, including 19,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.31 ( 7150 hom., cov: 32)

Exomes 𝑓: 0.32 ( 12145 hom. )

Consequence

NBN
NM_002485.5 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.123

Publications

26 publications found

Variant links:

Genes affected

NBN (HGNC:7652): (nibrin) Mutations in this gene are associated with Nijmegen breakage syndrome, an autosomal recessive chromosomal instability syndrome characterized by microcephaly, growth retardation, immunodeficiency, and cancer predisposition. The encoded protein is a member of the MRE11/RAD50 double-strand break repair complex which consists of 5 proteins. This gene product is thought to be involved in DNA double-strand break repair and DNA damage-induced checkpoint activation. [provided by RefSeq, Jul 2008]

NBN Gene-Disease associations (from GenCC):

Nijmegen breakage syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
rhabdomyosarcoma
Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
idiopathic aplastic anemia
Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
prostate cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
hereditary breast carcinoma
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

NBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 8-89935309-C-T is Benign according to our data. Variant chr8-89935309-C-T is described in ClinVar as Benign. ClinVar VariationId is 363909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.391 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.*273G>A		3_prime_UTR_variant	Exon 16 of 16	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.*273G>A		3_prime_UTR_variant	Exon 16 of 16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.305

AC:

46343

AN:

151726

Hom.:

7143

Cov.:

show subpopulations

Gnomad AFR

AF:

0.258

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.288

Gnomad ASJ

AF:

0.261

Gnomad EAS

AF:

0.406

Gnomad SAS

AF:

0.319

Gnomad FIN

AF:

0.306

Gnomad MID

AF:

0.263

Gnomad NFE

AF:

0.332

Gnomad OTH

AF:

0.300

GnomAD4 exome

AF:

0.319

AC:

73323

AN:

229508

Hom.:

12145

Cov.:

AF XY:

0.318

AC XY:

37880

AN XY:

119076

show subpopulations

African (AFR)

AF:

0.252

AC:

1868

AN:

7402

American (AMR)

AF:

0.290

AC:

2584

AN:

8922

Ashkenazi Jewish (ASJ)

AF:

0.263

AC:

2254

AN:

8558

East Asian (EAS)

AF:

0.408

AC:

7296

AN:

17888

South Asian (SAS)

AF:

0.289

AC:

7118

AN:

24638

European-Finnish (FIN)

AF:

0.307

AC:

2067

AN:

6742

Middle Eastern (MID)

AF:

0.268

AC:

286

AN:

1066

European-Non Finnish (NFE)

AF:

0.324

AC:

45416

AN:

140082

Other (OTH)

AF:

0.312

AC:

4434

AN:

14210

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

2418

4836

7254

9672

12090

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

290

580

870

1160

1450

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.305

AC:

46376

AN:

151844

Hom.:

7150

Cov.:

AF XY:

0.305

AC XY:

22615

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.258

AC:

10671

AN:

41420

American (AMR)

AF:

0.288

AC:

4398

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.261

AC:

905

AN:

3470

East Asian (EAS)

AF:

0.405

AC:

2088

AN:

5150

South Asian (SAS)

AF:

0.321

AC:

1549

AN:

4826

European-Finnish (FIN)

AF:

0.306

AC:

3210

AN:

10488

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.332

AC:

22539

AN:

67914

Other (OTH)

AF:

0.297

AC:

627

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1657

3315

4972

6630

8287

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

472

944

1416

1888

2360

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.316

Hom.:

21050

Bravo

AF:

0.298

Asia WGS

AF:

0.306

AC:

1063

AN:

3470

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 24, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Microcephaly, normal intelligence and immunodeficiency

Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

3.4

(source)

DANN

Benign

0.62

PhyloP100

0.12

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over