rs72563785

chr8-89943291-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_002485.5(NBN):c.2146A>G(p.Asn716Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00145 in 1,613,746 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. N716N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0076 (17 hom., cov: 32)
  • Exomes 𝑓: 0.00080 (17 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15 O:1
• Conservation: PhyloP100: 3.72

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005399674).
• BP6: Variant 8-89943291-T-C is Benign according to our data. Variant chr8-89943291-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 134874.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89943291-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00764 (1164/152280) while in subpopulation AFR AF= 0.027 (1122/41552). AF 95% confidence interval is 0.0257. There are 17 homozygotes in gnomad4. There are 539 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 17 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.2146A>G	p.Asn716Asp	missense_variant	14/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.2146A>G	p.Asn716Asp	missense_variant	14/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.00760 AC: 1157 AN: 152162 Hom.: 17 Cov.: 32

Gnomad AFR AF: 0.0269

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00196 AC: 493 AN: 251350 Hom.: 7 AF XY: 0.00150 AC XY: 204 AN XY: 135840

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000792

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000801 AC: 1170 AN: 1461466 Hom.: 17 Cov.: 31 AF XY: 0.000707 AC XY: 514 AN XY: 727048

Gnomad4 AFR exome AF: 0.0287

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.00157

GnomAD4 genome AF: 0.00764 AC: 1164 AN: 152280 Hom.: 17 Cov.: 32 AF XY: 0.00724 AC XY: 539 AN XY: 74488

Gnomad4 AFR AF: 0.0270

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00141 Hom.: 1

Bravo AF: 0.00894

ESP6500AA AF: 0.0266 AC: 117

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00243 AC: 295

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:15 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 19, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Sep 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 25, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 23, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NBN p.Asn716Asp variant was identified in 1 of 164 proband chromosomes (frequency: 0.006) from individuals or families with cancer and was present in 5 of 1362 control chromosomes (frequency: 0.004) from healthy individuals (Wang 2013, Bodian 2014). The variant was also identified in the following databases: dbSNP (ID: rs72563785) as "With other allele", ClinVar (5x benign, 1x uncertain significance), Clinvitae, and Zhejiang Colon Cancer Database. The variant was not identified in the Cosmic or LOVD 3.0 databases. The variant was identified in control databases in 716 of 277088 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017). The variant was identified in the following populations at a frequency greater than 1%: African in 651 of 24032 chromosomes (freq: 0.03). The p.Asn716 residue is conserved in mammals but not in more distantly related organisms. However four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -

Microcephaly, normal intelligence and immunodeficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Hereditary cancer-predisposing syndrome Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 2014	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 11, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Vantari Genetics	Feb 04, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2016	Variant summary: The c.2146A>G variant affects a conserved nucleotide, resulting in amino acid change from Asn to Asp. 3/4 in-silico tools predict this variant to be benign. This variant is found in 295/121388 control chromosomes (including 5 homozygotes) at a frequency of 0.0024302. It was predominantly observed in the African subpopulation at a frequency of 2.7% including 5 homozygous occurrences. This frequency significantly exceeds the maximal expected allele frequency for a pathogenic variant in NBN (0.25%), suggesting this is a benign polymorphism found primarily in population(s) of African origin. In addition, multiple clinical laboratories have classified this variant as benign/likely benign. One internal sample with this variant also carried a deleterious variant PMS2 c.2186_2187delTC, supporting bening outcome. Taken together, this variant has been classified as Benign. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 06, 2023	- -

Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 25, 2022

- -

Hereditary breast ovarian cancer syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Apr 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.56
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;.
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.78	T;D;T
MetaRNN	Benign	0.0054	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.5	L;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N;N;.
REVEL	Benign	0.15
Sift	Benign	0.085	T;T;.
Sift4G	Benign	0.10	T;T;T
Polyphen		0.14	B;.;.
Vest4		0.16
MVP		0.70
MPC		0.21
ClinPred		0.015	T
GERP RS		5.8
Varity_R		0.20
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs72563785; hg19: chr8-90955519; COSMIC: COSV99038427; COSMIC: COSV99038427;