rs147626427
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS1
The NM_002485.5(NBN):c.788T>C(p.Phe263Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000105 in 1,614,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00056 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000057 ( 0 hom. )
Consequence
NBN
NM_002485.5 missense
NM_002485.5 missense
Scores
1
11
7
Clinical Significance
Conservation
PhyloP100: 4.29
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
BP4
Computational evidence support a benign effect (MetaRNN=0.15577173).
BP6
Variant 8-89970472-A-G is Benign according to our data. Variant chr8-89970472-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 127880.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=3, Benign=1}.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000565 (86/152330) while in subpopulation AFR AF= 0.00202 (84/41572). AF 95% confidence interval is 0.00167. There are 0 homozygotes in gnomad4. There are 41 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 | c.788T>C | p.Phe263Ser | missense_variant | 7/16 | ENST00000265433.8 | NP_002476.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.788T>C | p.Phe263Ser | missense_variant | 7/16 | 1 | NM_002485.5 | ENSP00000265433.4 |
Frequencies
GnomAD3 genomes AF: 0.000565 AC: 86AN: 152212Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000167 AC: 42AN: 251296Hom.: 0 AF XY: 0.000177 AC XY: 24AN XY: 135810
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GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461684Hom.: 0 Cov.: 31 AF XY: 0.0000605 AC XY: 44AN XY: 727146
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GnomAD4 genome AF: 0.000565 AC: 86AN: 152330Hom.: 0 Cov.: 32 AF XY: 0.000550 AC XY: 41AN XY: 74490
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:6
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not specified Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 18, 2019 | Variant summary: NBN c.788T>C (p.Phe263Ser) 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 0.00019 in 277060 control chromosomes, predominantly at a frequency of 0.0022 within the African subpopulation in the gnomAD database. The observed variant frequency within African control individuals in the gnomAD database is approximately 17.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African origin. c.788T>C has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Castera_2014, Haiman_2013, Tung_2014). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.2808_2811delACAA, p.Ala938fsX21), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six 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 likely benign. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Apr 27, 2016 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 09, 2022 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Nov 09, 2023 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in individuals with a personal or family history of breast, ovarian, and other cancers (PMID: 23555315, 24549055, 25186627, 36346689); This variant is associated with the following publications: (PMID: 24549055, 25186627, 23555315, 34072463, 24894818, 36346689) - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 21, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 13, 2021 | 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. - |
Microcephaly, normal intelligence and immunodeficiency Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
NBN-related disorder Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | Sep 21, 2024 | The NBN c.788T>C variant is predicted to result in the amino acid substitution p.Phe263Ser. This variant has been reported in multiple individuals in hereditary breast or ovarian cancer cohorts, as well as in a pan-cancer cohort; however, no additional functional studies or family segregation data are available to support its pathogenicity (Table S1, Castéra et al. 2014. PubMed ID: 24549055; Haiman et al. 2013. PubMed ID: 23555315; Tung et al. 2015. PubMed ID: 25186627; Belhadj et al. 2023. PubMed ID: 36346689). This variant is reported in 0.21% of alleles in individuals of African descent in gnomAD, a frequency higher than expected for a pathogenic allele in this gene. It has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from benign to a variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/127880/). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
T;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;T
M_CAP
Uncertain
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
T
MutationAssessor
Uncertain
M;.
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Uncertain
D;D
Polyphen
D;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at