rs769414

Positions:

chr8-89980789-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_002485.5(NBN):c.425A>G(p.Asn142Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 0 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:7O:1

Conservation

PhyloP100: 0.114

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05121094).

BP6

Variant 8-89980789-T-C is Benign according to our data. Variant chr8-89980789-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127871.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Benign=1, not_provided=1, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000198 (290/1461318) while in subpopulation MID AF= 0.00746 (43/5764). AF 95% confidence interval is 0.00569. There are 0 homozygotes in gnomad4_exome. There are 155 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5 linkuse as main transcript	c.425A>G	p.Asn142Ser	missense_variant	4/16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 linkuse as main transcript	c.425A>G	p.Asn142Ser	missense_variant	4/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0191

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000167

AC:

AN:

251294

Hom.:

AF XY:

0.000184

AC XY:

AN XY:

135820

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000202

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000198

AC:

290

AN:

1461318

Hom.:

Cov.:

AF XY:

0.000213

AC XY:

155

AN XY:

727018

show subpopulations

Gnomad4 AFR exome

AF:

0.000359

Gnomad4 AMR exome

AF:

0.000604

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000151

Gnomad4 OTH exome

AF:

0.000629

GnomAD4 genome

AF:

0.000335

AC:

AN:

152302

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000265

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000139

Hom.:

Bravo

AF:

0.000336

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000132

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3476

EpiCase

AF:

0.000382

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:7Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	May 15, 2023	In the published literature, this variant has been reported in individuals with breast and/or ovarian cancer (PMIDs: 34646395 (2021) and 26315354 (2015)), chronic myelomonocytic leukemia (PMID: 26979391 (2016)), as well as unaffected individuals (PMID: 24728327 (2014), 24894818 (2014), 26315354 (2015), 31206626 (2019)). The frequency of this variant in the general population, 0.00042 (15/35422 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 23, 2020	This variant is associated with the following publications: (PMID: 23525077, 26315354, 24728327, 26787654, 24894818, 26979391, 26193622, 12376507, 12427538, 31278556) -
Uncertain significance, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 02, 2017	- -

Microcephaly, normal intelligence and immunodeficiency

Uncertain:1Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

not specified

Uncertain:1Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 25, 2024	Variant summary: NBN c.425A>G (p.Asn142Ser) results in a conservative amino acid change located in the BRCT domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 258668 control chromosomes, predominantly at a frequency of 0.00043 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 3.44 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (0.00013). This variant has also been reported in the FLOSSIES database among women older than age 70 who have never had cancer. c.425A>G has been reported in the literature as a non-deleterious variant or a VUS in settings of multigene panel testing among individuals affected with breast and/or ovarian cancer (example, Ramus_2015, Young_2016, Weitzel_2019, Laraqui_2021, deOlivier_2022) and in at least one patient with hypogammaglobulinemia and lymphoma (example: Allain_2023). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36155879, 24728327, 23525077, 34646395, 12376507, 31278556, 26315354, 12427538, 31206626, 26787654, 35534704). ClinVar contains an entry for this variant (Variation ID: 127871). Based on the evidence outlined above, the variant was classified as likely benign. -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 17, 2015	- -

Hereditary cancer-predisposing syndrome

Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jun 21, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 19, 2021	This alteration is classified as likely 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. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2017

- -

Malignant tumor of breast

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

The NBN p.Asn142Ser variant was identified in 4 of 9094 proband chromosomes (frequency: 0.0004) from individuals or families with myeloproliferative neoplasms, epithelial ovarian cancer, or breast cancer and in 4 of 8224 control chromosomes (frequency: 0.0005) from healthy individuals (Bodian 2014, Pratz 2016, Ramus 2015, Young 2016). The variant was also identified in dbSNP (ID: rs769414) as "With other allele", ClinVar (classified as likely benign by Invitae and GeneDx; and as uncertain significance by Ambry Genetics and four other clinical laboratories), Cosmic (1x in oesophagus), LOVD 3.0 (1x), and Zhejiang University database. The variant was identified in control databases in 47 of 277032 chromosomes at a frequency of 0.0002 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: European in 24 of 126600 chromosomes (freq: 0.0002), African in 1 of 24028 chromosomes (freq: 0.00004), Other in 7 of 6460 chromosomes (freq: 0.001), Latino in 12 of 34412 chromosomes (freq: 0.0004), Ashkenazi Jewish in 2 of 10148 chromosomes (freq: 0.0002), and South Asian in 1 of 30782 chromosomes (freq: 0.00003); it was not observed in the East Asian or Finnish populations. The p.Asn142 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. The variant occurs outside of the splicing consensus sequence and 2 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.098

T;T;.;.

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.83

T;T;D;D

M_CAP

Benign

0.0096

MetaRNN

Benign

0.051

T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.43

N;.;.;.

MutationTaster

Benign

0.66

N;N

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Benign

0.034

Sift

Benign

0.39

T;T;T;T

Sift4G

Benign

0.84

T;T;.;T

Polyphen

0.13

B;.;.;.

Vest4

0.079

MVP

0.74

MPC

0.057

ClinPred

0.012

GERP RS

-1.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.031

gMVP

0.13

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over