8-89955634-G-T

Variant names:

• chr8-89955634-G-T
• rs1805786
• NM_002485.5:c.1125-79C>A

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.1125-79C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.335 in 1,428,956 control chromosomes in the GnomAD database, including 81,713 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.33 (8373 hom., cov: 32)
  • Exomes 𝑓: 0.34 (73340 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.645
• Publications: 8 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=-0.83).
• BP6: Variant 8-89955634-G-T is Benign according to our data. Variant chr8-89955634-G-T is described in ClinVar as Benign. ClinVar VariationId is 1239473.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.1125-79C>A		intron_variant	Intron 9 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.1125-79C>A		intron_variant	Intron 9 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.331 AC: 50199 AN: 151750 Hom.: 8364 Cov.: 32

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.350

Gnomad ASJ AF: 0.315

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.436

Gnomad FIN AF: 0.354

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.322

Gnomad OTH AF: 0.339

GnomAD4 exome AF: 0.336 AC: 428632 AN: 1277088 Hom.: 73340 AF XY: 0.338 AC XY: 215756 AN XY: 639170

African (AFR) AF: 0.309 AC: 8769 AN: 28400

American (AMR) AF: 0.354 AC: 12323 AN: 34792

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 7606 AN: 24126

East Asian (EAS) AF: 0.480 AC: 17791 AN: 37044

South Asian (SAS) AF: 0.426 AC: 32855 AN: 77066

European-Finnish (FIN) AF: 0.358 AC: 14776 AN: 41302

Middle Eastern (MID) AF: 0.345 AC: 1410 AN: 4082

European-Non Finnish (NFE) AF: 0.322 AC: 314608 AN: 976294

Other (OTH) AF: 0.343 AC: 18494 AN: 53982

GnomAD4 genome AF: 0.331 AC: 50233 AN: 151868 Hom.: 8373 Cov.: 32 AF XY: 0.336 AC XY: 24895 AN XY: 74196

African (AFR) AF: 0.307 AC: 12706 AN: 41412

American (AMR) AF: 0.351 AC: 5349 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.315 AC: 1090 AN: 3464

East Asian (EAS) AF: 0.452 AC: 2336 AN: 5172

South Asian (SAS) AF: 0.437 AC: 2112 AN: 4828

European-Finnish (FIN) AF: 0.354 AC: 3719 AN: 10518

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.322 AC: 21869 AN: 67902

Other (OTH) AF: 0.343 AC: 724 AN: 2110

Alfa AF: 0.333 Hom.: 1125

Bravo AF: 0.326

Asia WGS AF: 0.425 AC: 1478 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	5.6
DANN	Benign	0.29
PhyloP100		0.65
Mutation Taster		=100/0	polymorphism (auto)

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: rs1805786; hg19: chr8-90967862; COSMIC: COSV55376816; COSMIC: COSV55376816;