Genetic Variant NBN:c.37+5G>A (chr8-89984520-C-T) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_002485.5(NBN):c.37+5G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,612,808 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 12 hom., cov: 33)

Exomes 𝑓: 0.0014 ( 17 hom. )

Consequence

NBN
NM_002485.5 splice_region, intron

Scores

Splicing: ADA: 0.8241

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:18

Conservation

PhyloP100: 0.881

Publications

4 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:

ENSG00000309953 (HGNC:):

ENSG00000309953 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 8-89984520-C-T is Benign according to our data. Variant chr8-89984520-C-T is described in ClinVar as Benign. ClinVar VariationId is 140918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00711 (1083/152372) while in subpopulation AFR AF = 0.0222 (923/41592). AF 95% confidence interval is 0.021. There are 12 homozygotes in GnomAd4. There are 517 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002485.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NBN	NM_002485.5	MANE Select	c.37+5G>A	splice_region intron	N/A	NP_002476.2
NBN	NM_001024688.3		c.-260+5G>A	splice_region intron	N/A	NP_001019859.1
NBN	NM_001440379.1		c.-522G>A	upstream_gene	N/A	NP_001427308.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
NBN	ENST00000265433.8	TSL:1 MANE Select	c.37+5G>A	splice_region intron	N/A	ENSP00000265433.4
NBN	ENST00000697309.1		c.37+5G>A	splice_region intron	N/A	ENSP00000513244.1
NBN	ENST00000697293.1		c.37+5G>A	splice_region intron	N/A	ENSP00000513230.1

Frequencies

GnomAD3 genomes

AF:

0.00711

AC:

1082

AN:

152254

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0222

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00556

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000565

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000764

Gnomad OTH

AF:

0.00766

GnomAD2 exomes

AF:

0.00222

AC:

545

AN:

245710

AF XY:

0.00170

show subpopulations

Gnomad AFR exome

AF:

0.0232

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000110

Gnomad FIN exome

AF:

0.000894

Gnomad NFE exome

AF:

0.000957

Gnomad OTH exome

AF:

0.00199

GnomAD4 exome

AF:

0.00136

AC:

1993

AN:

1460436

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

911

AN XY:

726610

show subpopulations

African (AFR)

AF:

0.0232

AC:

777

AN:

33442

American (AMR)

AF:

0.00188

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39690

South Asian (SAS)

AF:

0.0000812

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00123

AC:

AN:

52912

Middle Eastern (MID)

AF:

0.000696

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.000831

AC:

923

AN:

1111320

Other (OTH)

AF:

0.00219

AC:

132

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

102

204

305

407

509

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

156

208

260

<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:

0.00711

AC:

1083

AN:

152372

Hom.:

Cov.:

AF XY:

0.00694

AC XY:

517

AN XY:

74508

show subpopulations

African (AFR)

AF:

0.0222

AC:

923

AN:

41592

American (AMR)

AF:

0.00555

AC:

AN:

15314

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000565

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000764

AC:

AN:

68030

Other (OTH)

AF:

0.00758

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

117

176

234

293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00484

Hom.:

Bravo

AF:

0.00808

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000600

EpiControl

AF:

0.000593

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly, normal intelligence and immunodeficiency (5)

not provided (4)

Hereditary cancer-predisposing syndrome (3)

not specified (3)

Acute lymphoid leukemia (1)

Hereditary breast ovarian cancer syndrome (1)

Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.85

PhyloP100

0.88

PromoterAI

-0.48

Neutral

(source)

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.82

dbscSNV1_RF

Benign

0.55

SpliceAI score (max)

0.12

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over