chr8-89981412-C-T

Variant names:

• chr8-89981412-C-T
• rs61753720
• NM_002485.5:c.283G>A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002485.5(NBN):​c.283G>A​(p.Asp95Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00226 in 1,614,012 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (4 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:20 O:1
• Conservation: PhyloP100: 4.11

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.02321592).
• BP6: Variant 8-89981412-C-T is Benign according to our data. Variant chr8-89981412-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127869.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=6, Likely_benign=8, not_provided=1}. Variant chr8-89981412-C-T is described in Lovd as [Likely_benign]. Variant chr8-89981412-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00183 (279/152300) while in subpopulation NFE AF= 0.0031 (211/68022). AF 95% confidence interval is 0.00276. There are 0 homozygotes in gnomad4. There are 116 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 4 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.283G>A	p.Asp95Asn	missense_variant	Exon 3 of 16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.283G>A	p.Asp95Asn	missense_variant	Exon 3 of 16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.00183 AC: 279 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00310

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00173 AC: 435 AN: 251380 Hom.: 1 AF XY: 0.00172 AC XY: 234 AN XY: 135878

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00407

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000392

Gnomad FIN exome AF: 0.000370

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00231 AC: 3373 AN: 1461712 Hom.: 4 Cov.: 31 AF XY: 0.00224 AC XY: 1627 AN XY: 727148

Gnomad4 AFR exome AF: 0.000388

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.00429

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.000375

Gnomad4 NFE exome AF: 0.00275

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00183 AC: 279 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.00156 AC XY: 116 AN XY: 74468

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00310

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00301 Hom.: 0

Bravo AF: 0.00182

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00208 AC: 8

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00256 AC: 22

ExAC AF: 0.00186 AC: 226

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00333

EpiControl AF: 0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:20 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:7

Aug 02, 2019

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 26, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Oct 06, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS1 -

Apr 18, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The variant of interest causes a missense change involving a conserved nucleotide with 3/4 in silico programs (SNPs&GO not captured here due to low reliability index) predict a "deleterious" outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 225/121130 (1/538), which exceeds the predicted maximum expected allele frequency for a pathogenic NBN variant of 1/8000 for HBOC. The variant of interest has been reported in multiple affected individuals (ALL, OvC, BrC) with limited information ie lack of co-occurrence and co-segregation data. In addition, multiple reputable clinical laboratories cite the variant with a classification of "likely benign/benign." Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as Benign. -

Jun 15, 2017

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NBN: BP1, BS1 -

Microcephaly, normal intelligence and immunodeficiency Uncertain:1 Benign:5

Jan 15, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 18, 2021

Genome-Nilou Lab

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Aug 19, 2020

St. Jude Molecular Pathology, St. Jude Children's Research Hospital

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 02, 2018

Mendelics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:5 Other:1

Jan 10, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

-

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

The NBN p.Asp95Asn variant was identified in 15 of 7572 proband chromosomes (frequency: 0.002) from individuals with breast, larynx cancer and acute lymphoblastic leukemia and was present in 14 of 8336 control chromosomes (frequency: 0.002) from healthy individuals (Desjardins 2009, Ziolkowska 2007, Varon 2011, Ramus 2015). The variant was identified in dbSNP (rs61753720) as “with uncertain significance, other allele” also identified in ClinVar (interpreted as "likely benign" by GeneDx and 6 others, "benign" by Invitae and 3 others, "uncertain significance" by 2 others) and LOVD 3.0 (observed 4x). The variant was identified in control databases in 477 of 277,154 chromosomes (1 homozygous) at a frequency of 0.002 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 18 of 24,028 chromosomes (freq: 0.0007), Other in 7 of 6466 chromosomes (freq: 0.001), Latino in 22 of 34,414 chromosomes (freq: 0.0006), European in 365 of 126,674 chromosomes (freq: 0.003), Ashkenazi Jewish in 40 of 10,150 chromosomes (freq: 0.004), Finnish in 13 of 25,784 chromosomes (freq: 0.0005), and South Asian in 12 of 30,778 chromosomes (freq: 0.0004). The variant was not observed in the East Asian population. In the control population, the variant exceeds the maximum expected allele frequency (0.0001) for a pathogenic NBN variant leading to the likelihood of a benign classification. The p.Asp95 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. -

May 27, 2021

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2017

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Benign:3

Feb 14, 2018

True Health Diagnostics

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jul 24, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Apr 13, 2021

Sema4, Sema4

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: curation

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.59	D;T;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Uncertain	0.093	D
MetaRNN	Benign	0.023	T;T;T;T;T
MetaSVM	Uncertain	0.49	D
MutationAssessor	Pathogenic	3.3	M;.;.;.;.
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-4.3	D;D;D;D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.012	D;D;D;D;D
Sift4G	Uncertain	0.040	D;T;T;.;T
Polyphen		1.0	D;.;.;.;.
Vest4		0.59
MVP		0.87
MPC		0.40
ClinPred		0.063	T
GERP RS		4.8
Varity_R		0.61
gMVP		0.70

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: rs61753720; hg19: chr8-90993640; COSMIC: COSV104545419; COSMIC: COSV104545419;