rs3026271

Variant names:

• chr8-89971024-A-G
• rs3026271
• NM_002485.5:c.702+149T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002485.5(NBN):​c.702+149T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0531 in 728,674 control chromosomes in the GnomAD database, including 1,341 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (222 hom., cov: 32)
  • Exomes 𝑓: 0.056 (1119 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.71
• Publications: 7 publications found

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 8-89971024-A-G is Benign according to our data. Variant chr8-89971024-A-G is described in ClinVar as [Benign]. Clinvar id is 1263646.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0655 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.702+149T>C		intron_variant	Intron 6 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.702+149T>C		intron_variant	Intron 6 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.0432 AC: 6575 AN: 152174 Hom.: 222 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.0526

Gnomad AMR AF: 0.0373

Gnomad ASJ AF: 0.0444

Gnomad EAS AF: 0.000770

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0521

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0672

Gnomad OTH AF: 0.0320

GnomAD4 exome AF: 0.0557 AC: 32123 AN: 576382 Hom.: 1119 AF XY: 0.0551 AC XY: 16667 AN XY: 302258

African (AFR) AF: 0.0120 AC: 178 AN: 14772

American (AMR) AF: 0.0337 AC: 680 AN: 20186

Ashkenazi Jewish (ASJ) AF: 0.0458 AC: 663 AN: 14472

East Asian (EAS) AF: 0.000170 AC: 5 AN: 29462

South Asian (SAS) AF: 0.0420 AC: 2082 AN: 49578

European-Finnish (FIN) AF: 0.0470 AC: 1326 AN: 28222

Middle Eastern (MID) AF: 0.0605 AC: 128 AN: 2114

European-Non Finnish (NFE) AF: 0.0657 AC: 25520 AN: 388500

Other (OTH) AF: 0.0530 AC: 1541 AN: 29076

GnomAD4 genome AF: 0.0431 AC: 6571 AN: 152292 Hom.: 222 Cov.: 32 AF XY: 0.0423 AC XY: 3147 AN XY: 74466

African (AFR) AF: 0.0105 AC: 435 AN: 41576

American (AMR) AF: 0.0371 AC: 568 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0444 AC: 154 AN: 3468

East Asian (EAS) AF: 0.000771 AC: 4 AN: 5186

South Asian (SAS) AF: 0.0315 AC: 152 AN: 4828

European-Finnish (FIN) AF: 0.0521 AC: 553 AN: 10612

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0672 AC: 4568 AN: 68000

Other (OTH) AF: 0.0312 AC: 66 AN: 2114

Alfa AF: 0.0501 Hom.: 27

Bravo AF: 0.0409

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.6
DANN	Benign	0.32
PhyloP100		1.7
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: rs3026271; hg19: chr8-90983252;