rs3736640

Variant names:

• chr8-89943427-T-A
• rs3736640
• NM_002485.5:c.2071-61A>T

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.2071-61A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0367 in 1,486,034 control chromosomes in the GnomAD database, including 1,333 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.042 (188 hom., cov: 32)
  • Exomes 𝑓: 0.036 (1145 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.777
• Publications: 6 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=-0.97).
• BP6: Variant 8-89943427-T-A is Benign according to our data. Variant chr8-89943427-T-A is described in ClinVar as [Benign]. Clinvar id is 1226117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0906 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.2071-61A>T		intron_variant	Intron 13 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.2071-61A>T		intron_variant	Intron 13 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.0416 AC: 6325 AN: 152136 Hom.: 184 Cov.: 32

Gnomad AFR AF: 0.0605

Gnomad AMI AF: 0.00987

Gnomad AMR AF: 0.0507

Gnomad ASJ AF: 0.0372

Gnomad EAS AF: 0.0543

Gnomad SAS AF: 0.0971

Gnomad FIN AF: 0.00980

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0285

Gnomad OTH AF: 0.0492

GnomAD4 exome AF: 0.0361 AC: 48188 AN: 1333780 Hom.: 1145 Cov.: 22 AF XY: 0.0379 AC XY: 25380 AN XY: 669778

African (AFR) AF: 0.0589 AC: 1786 AN: 30348

American (AMR) AF: 0.0505 AC: 2214 AN: 43874

Ashkenazi Jewish (ASJ) AF: 0.0409 AC: 1035 AN: 25280

East Asian (EAS) AF: 0.0669 AC: 2589 AN: 38700

South Asian (SAS) AF: 0.0913 AC: 7584 AN: 83072

European-Finnish (FIN) AF: 0.00848 AC: 415 AN: 48920

Middle Eastern (MID) AF: 0.0408 AC: 222 AN: 5442

European-Non Finnish (NFE) AF: 0.0301 AC: 30132 AN: 1002050

Other (OTH) AF: 0.0394 AC: 2211 AN: 56094

GnomAD4 genome AF: 0.0417 AC: 6346 AN: 152254 Hom.: 188 Cov.: 32 AF XY: 0.0410 AC XY: 3051 AN XY: 74446

African (AFR) AF: 0.0605 AC: 2512 AN: 41540

American (AMR) AF: 0.0508 AC: 777 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0372 AC: 129 AN: 3468

East Asian (EAS) AF: 0.0540 AC: 280 AN: 5182

South Asian (SAS) AF: 0.0978 AC: 472 AN: 4824

European-Finnish (FIN) AF: 0.00980 AC: 104 AN: 10610

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0285 AC: 1939 AN: 68008

Other (OTH) AF: 0.0553 AC: 117 AN: 2116

Alfa AF: 0.0352 Hom.: 21

Bravo AF: 0.0451

Asia WGS AF: 0.101 AC: 353 AN: 3476

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

- -

Hereditary breast ovarian cancer syndrome Benign:1

Apr 19, 2022

National Health Laboratory Service, Universitas Academic Hospital and University of the Free State

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.0060
DANN	Benign	0.42
PhyloP100		-0.78
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: rs3736640; hg19: chr8-90955655;