rs777460725

Positions:

chr8-89971192-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 0P and 0B.

The ENST00000265433.8(NBN):c.683T>G(p.Ile228Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000794 in 1,612,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I228M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000084 ( 0 hom. )

Consequence

NBN
ENST00000265433.8 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:12

Conservation

PhyloP100: 7.08

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 Uncertain_significance. Variant got 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5 linkuse as main transcript	c.683T>G	p.Ile228Arg	missense_variant	6/16	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.683T>G	p.Ile228Arg	missense_variant	6/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000679

AC:

AN:

250470

Hom.:

AF XY:

0.0000591

AC XY:

AN XY:

135432

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000835

AC:

122

AN:

1460654

Hom.:

Cov.:

AF XY:

0.0000757

AC XY:

AN XY:

726634

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.0000990

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74368

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000107

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces isoleucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 228 of the NBN protein (p.Ile228Arg). This variant is present in population databases (rs777460725, gnomAD 0.01%). This missense change has been observed in individual(s) with Lynch syndrome (PMID: 25980754). This missense change has been observed to co-occur in individuals with a different variant in NBN that has been determined to be pathogenic (Invitae), but the significance of this finding is unclear. ClinVar contains an entry for this variant (Variation ID: 186350). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 10, 2024	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Published functional studies demonstrate loss of protein stability and sensitivity to mitomycin-C similar to a positive control (PMID: 37503171); Observed in individuals with breast cancer, Lynch-syndrome associated cancer and/or polyps, or B-cell acute lymphoblastic leukemia (PMID: 33471991, 25980754, 37503171); This variant is associated with the following publications: (PMID: 33471991, 25980754, 24894818, 37503171, 36346689, 38446568) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Mar 19, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 22, 2019	The NBN c.683T>G, p.(Ile228Arg) variant (rs777460725), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 186350). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.007 percent (identified on 20 out of 281,876 chromosomes). The isoleucine at position 228 is weakly conserved and computational analyses of the effects of the p.(Ile228Arg) variant on protein structure and function is deleterious (SIFT: damaging, PolyPhen-2: possibly damaging). Altogether, there is not enough evidence to classify the p.(Ile228Arg) variant with certainty. -

Hereditary cancer-predisposing syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	curation	Sema4, Sema4	Jun 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Ambry Genetics	May 10, 2023	The p.I228R variant (also known as c.683T>G), located in coding exon 6 of the NBN gene, results from a T to G substitution at nucleotide position 683. The isoleucine at codon 228 is replaced by arginine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Oct 31, 2018

- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Mar 28, 2019

Variant summary: NBN c.683T>G (p.Ile228Arg) results in a non-conservative amino acid change located in the Nibrin, second BRCT domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 6.5e-05 in 276394 control chromosomes (gnomAD). This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (6.5e-05 vs 0.0025), allowing no conclusion about variant significance. The variant, c.683T>G, has been reported in the literature in an individual being tested for Lynch Syndrome (Yurgelun_2015). These report does not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Aplastic anemia

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 04, 2024

- -

NBN-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 11, 2024

The NBN c.683T>G variant is predicted to result in the amino acid substitution p.Ile228Arg. This variant has been reported as a variant of uncertain significance in an individual undergoing testing for Lynch syndrome (Table S2, Yurgelun et al. 2015. PubMed ID: 25980754). This variant has also been reported as a variant of uncertain significance in a study of NBN as a pan-cancer susceptibility gene (Table S2, Belhadj et al. 2023. PubMed ID: 36346689). This variant is reported in 0.012% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has been interpreted as a variant of uncertain significance in the ClinVar database (https://www.ncbi.nlm.nih.gov/clinvar/variation/186350/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Uncertain

0.073

BayesDel_noAF

Uncertain

0.070

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.44

T;T;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;T;D;D

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.56

D;D;D;D

MetaSVM

Uncertain

-0.25

MutationAssessor

Benign

2.0

M;.;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.34

PROVEAN

Pathogenic

-5.0

D;D;D;D

REVEL

Uncertain

0.54

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0030

D;D;D;.

Polyphen

0.95

P;.;.;.

Vest4

0.68

MutPred

0.69

Gain of disorder (P = 0.012);.;.;.;

MVP

0.92

MPC

0.34

ClinPred

0.43

GERP RS

5.8

Varity_R

0.77

gMVP

0.87

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