8-89953700-T-TA

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_002485.5(NBN):c.1398-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000479 in 1,580,906 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00048 ( 3 hom. )

Consequence

NBN
NM_002485.5 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.25

Publications

1 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 -16 ACMG points.

BP6

Variant 8-89953700-T-TA is Benign according to our data. Variant chr8-89953700-T-TA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 132766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000479 (685/1429888) while in subpopulation MID AF = 0.0092 (49/5326). AF 95% confidence interval is 0.00715. There are 3 homozygotes in GnomAdExome4. There are 373 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.1398-10dupT		intron_variant	Intron 10 of 15	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.1398-10dupT		intron_variant	Intron 10 of 15	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.000477

AC:

AN:

150904

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000341

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000331

Gnomad ASJ

AF:

0.00377

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00167

Gnomad FIN

AF:

0.0000967

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.000325

Gnomad OTH

AF:

0.00193

GnomAD2 exomes

AF:

0.000913

AC:

186

AN:

203826

AF XY:

0.000991

show subpopulations

Gnomad AFR exome

AF:

0.000464

Gnomad AMR exome

AF:

0.000883

Gnomad ASJ exome

AF:

0.00366

Gnomad EAS exome

AF:

0.000256

Gnomad FIN exome

AF:

0.000588

Gnomad NFE exome

AF:

0.000474

Gnomad OTH exome

AF:

0.00101

GnomAD4 exome

AF:

0.000479

AC:

685

AN:

1429888

Hom.:

Cov.:

AF XY:

0.000524

AC XY:

373

AN XY:

711362

show subpopulations

African (AFR)

AF:

0.000399

AC:

AN:

32554

American (AMR)

AF:

0.000843

AC:

AN:

42698

Ashkenazi Jewish (ASJ)

AF:

0.00266

AC:

AN:

25556

East Asian (EAS)

AF:

0.000153

AC:

AN:

39220

South Asian (SAS)

AF:

0.00209

AC:

175

AN:

83854

European-Finnish (FIN)

AF:

0.000182

AC:

AN:

49420

Middle Eastern (MID)

AF:

0.00920

AC:

AN:

5326

European-Non Finnish (NFE)

AF:

0.000260

AC:

284

AN:

1092198

Other (OTH)

AF:

0.000762

AC:

AN:

59062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.416

Heterozygous variant carriers

118

147

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000477

AC:

AN:

151018

Hom.:

Cov.:

AF XY:

0.000502

AC XY:

AN XY:

73764

show subpopulations

African (AFR)

AF:

0.000340

AC:

AN:

41230

American (AMR)

AF:

0.000330

AC:

AN:

15130

Ashkenazi Jewish (ASJ)

AF:

0.00377

AC:

AN:

3450

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00167

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.0000967

AC:

AN:

10336

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000325

AC:

AN:

67620

Other (OTH)

AF:

0.00191

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000725

Hom.:

Bravo

AF:

0.000378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Aug 20, 2021

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 26, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: NBN c.1398-10dupT alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00048 in 1580906 control chromosomes, predominantly at a frequency of 0.0021 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.00048 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1398-10dupT in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 132766). Based on the evidence outlined above, the variant was classified as likely benign. -

Jun 07, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Apr 15, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Benign:2

Mar 14, 2024

Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 09, 2021

Sema4, Sema4

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

- -

Microcephaly, normal intelligence and immunodeficiency

Benign:1

Feb 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary breast ovarian cancer syndrome

Benign:1

Jan 15, 2019

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.3

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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