Genetic Variant ENST00000494804.2:n.5892G>A (chr8-89933257-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000494804.2(NBN):n.5892G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.317 in 183,692 control chromosomes in the GnomAD database, including 9,265 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7469 hom., cov: 33)

Exomes 𝑓: 0.33 ( 1796 hom. )

Consequence

NBN
ENST00000494804.2 non_coding_transcript_exon

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.305

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5 link	c.*2325G>A		downstream_gene_variant		ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 link	c.*2325G>A		downstream_gene_variant		1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes

AF:

0.313

AC:

47555

AN:

151950

Hom.:

7459

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.338

Gnomad AMR

AF:

0.292

Gnomad ASJ

AF:

0.261

Gnomad EAS

AF:

0.407

Gnomad SAS

AF:

0.318

Gnomad FIN

AF:

0.307

Gnomad MID

AF:

0.266

Gnomad NFE

AF:

0.333

Gnomad OTH

AF:

0.305

GnomAD4 exome

AF:

0.334

AC:

10565

AN:

31624

Hom.:

1796

AF XY:

0.333

AC XY:

4845

AN XY:

14558

show subpopulations

African (AFR)

AF:

0.283

AC:

318

AN:

1124

American (AMR)

AF:

0.325

AC:

246

AN:

758

Ashkenazi Jewish (ASJ)

AF:

0.272

AC:

555

AN:

2042

East Asian (EAS)

AF:

0.404

AC:

2425

AN:

5998

South Asian (SAS)

AF:

0.282

AC:

AN:

252

European-Finnish (FIN)

AF:

0.375

AC:

AN:

Middle Eastern (MID)

AF:

0.242

AC:

AN:

190

European-Non Finnish (NFE)

AF:

0.327

AC:

6114

AN:

18682

Other (OTH)

AF:

0.306

AC:

784

AN:

2562

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

324

647

971

1294

1618

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<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:

0.313

AC:

47593

AN:

152068

Hom.:

7469

Cov.:

AF XY:

0.312

AC XY:

23213

AN XY:

74334

show subpopulations

African (AFR)

AF:

0.281

AC:

11662

AN:

41478

American (AMR)

AF:

0.292

AC:

4457

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.261

AC:

904

AN:

3466

East Asian (EAS)

AF:

0.407

AC:

2103

AN:

5172

South Asian (SAS)

AF:

0.321

AC:

1547

AN:

4822

European-Finnish (FIN)

AF:

0.307

AC:

3238

AN:

10546

Middle Eastern (MID)

AF:

0.279

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.333

AC:

22653

AN:

67990

Other (OTH)

AF:

0.303

AC:

639

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1705

3411

5116

6822

8527

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

482

964

1446

1928

2410

<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:

0.326

Hom.:

2162

Bravo

AF:

0.307

Asia WGS

AF:

0.308

AC:

1074

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

(source)

DANN

Benign

0.74

PhyloP100

0.30

Splicing

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

Computational scores

Splicing

Publications

Other links and lift over