rs146605798

Positions:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS1

The NM_002485.5(NBN):c.1035C>T(p.Gly345Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000136 in 1,613,764 control chromosomes in the GnomAD database, including 1 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 0.00015 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

NBN
NM_002485.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:10

Conservation

PhyloP100: 1.12

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:

NBN (HGNC:):

NBN links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 8-89958814-G-A is Benign according to our data. Variant chr8-89958814-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127853.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=1, Benign=2}. Variant chr8-89958814-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=1.12 with no splicing effect.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000151 (23/152276) while in subpopulation EAS AF= 0.00386 (20/5186). AF 95% confidence interval is 0.00255. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. 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.1035C>T	p.Gly345Gly	synonymous_variant	9/16	ENST00000265433.8	NP_002476.2	O60934

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 linkuse as main transcript	c.1035C>T	p.Gly345Gly	synonymous_variant	9/16	1	NM_002485.5	ENSP00000265433.4		O60934

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000943

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000430

AC:

108

AN:

251366

Hom.:

AF XY:

0.000339

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00565

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000135

AC:

197

AN:

1461488

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00408

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00000900

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000151

AC:

AN:

152276

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00386

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000943

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000947

Bravo

AF:

0.000147

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:10

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NBN p.Gly345Gly variant was not identified in the literature nor was it identified in the Cosmic, LOVD 3.0, Zhejiang Colon Cancer databases. The variant was also identified in the following databases: dbSNP (ID: rs146605798) as â€šÃ„ÃºWith Likely benign, Uncertain significance alleleâ€šÃ„Ã¹, ClinVar (3x, as Benign by Invitae, likely benign by Amby Genetics and uncertain significance by GeneDx), Clinvitae (3x). The variant was identified in control databases in 109 of 277086 chromosomes at a frequency of 0.000393 in the following populations: â€šÃ„Ãºotherâ€šÃ„Ã¹ in 1 of 6466 chromosomes (freq. 0.00015), European in 1 of 126612 chromosomes (freq. 0.000008), East Asian in 104 of 18868 chromosomes (freq. 0.0055), Finnish in 3 of 25794 chromosomes (freq. 0.000116) (Genome Aggregation Consortium Feb 27, 2017). The p.Gly345Gly variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume 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 uncertain significance. -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 28, 2021	This variant is associated with the following publications: (PMID: 25980754) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	NBN: BP4, BP7 -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 16, 2016	Variant summary: The NBN c.1035C>T (p.Gly345Gly) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a benign outcome for this variant. multiple in silico models predict the formation of a cryptic donor site with a higher score than the canonocal splice donor site, however, these predictions have yet to be confirmed by functional studies. This variant was found in 59/121358 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0067021 (58/8654). This frequency is about 54 times the estimated maximal expected allele frequency of a pathogenic NBN variant (0.000125), suggesting this is likely a benign polymorphism found primarily in the populations of East Asian origin. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign/likely benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Jun 20, 2023	- -

Hereditary cancer-predisposing syndrome

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 17, 2014	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. -
Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Aug 22, 2017	- -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Nov 01, 2021	- -

Microcephaly, normal intelligence and immunodeficiency

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 27, 2019

- -

NBN-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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