8-89981412-C-T

Position:

chr8-89981412-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:20O:1

Conservation

PhyloP100: 4.11

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 -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: {Likely_benign=8, Benign=6, not_provided=1, Uncertain_significance=2}. 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/exons	MANE	Protein	UniProt
NBN	NM_002485.5 linkuse as main transcript	c.283G>A	p.Asp95Asn	missense_variant	3/16	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.283G>A	p.Asp95Asn	missense_variant	3/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes

AF:

0.00183

AC:

279

AN:

152182

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00172

AC XY:

234

AN XY:

135878

show subpopulations

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.:

Cov.:

AF XY:

0.00224

AC XY:

1627

AN XY:

727148

show subpopulations

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.:

Cov.:

AF XY:

0.00156

AC XY:

116

AN XY:

74468

show subpopulations

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.:

Bravo

AF:

0.00182

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.00186

AC:

226

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00333

EpiControl

AF:

0.00308

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:7

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	NBN: BP1, BS1 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 18, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 02, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 06, 2022	BS1 -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Jun 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 25, 2023	- -

Microcephaly, normal intelligence and immunodeficiency

Uncertain:1Benign:5

Likely benign, criteria provided, single submitter	clinical testing	St. Jude Molecular Pathology, St. Jude Children's Research Hospital	Aug 19, 2020	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 15, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 02, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -

not specified

Benign:5Other:1

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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 â€šÃ„Ãºwith uncertain significance, other alleleâ€šÃ„Ã¹ 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 27, 2021	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2018	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. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 28, 2017	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Apr 13, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Feb 14, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 24, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.59

D;T;.;.;.

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Uncertain

0.78

LIST_S2

Uncertain

0.89

D;D;D;D;D

M_CAP

Uncertain

0.093

MetaRNN

Benign

0.023

T;T;T;T;T

MetaSVM

Uncertain

0.49

MutationAssessor

Pathogenic

3.3

M;.;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.46

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

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

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