rs587780095
Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_002485.5(NBN):āc.254A>Gā(p.Asn85Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,614,062 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
Consequence
NM_002485.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.254A>G | p.Asn85Ser | missense_variant | 3/16 | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.254A>G | p.Asn85Ser | missense_variant | 3/16 | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000526 AC: 8AN: 152186Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000107 AC: 27AN: 251410Hom.: 0 AF XY: 0.000162 AC XY: 22AN XY: 135886
GnomAD4 exome AF: 0.0000691 AC: 101AN: 1461758Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 78AN XY: 727184
GnomAD4 genome ? AF: 0.0000525 AC: 8AN: 152304Hom.: 0 Cov.: 32 AF XY: 0.0000806 AC XY: 6AN XY: 74466
ClinVar
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 25, 2024 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 16, 2022 | In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Absent from cases but observed in controls in case-control studies assessing breast cancer, pancreatic cancer, or melanoma risk (Momozawa et al., 2018; Pritchard et al., 2018; Mizukami et al., 2020; Dorling et al., 2021); This variant is associated with the following publications: (PMID: 29641532, 30287823, 32980694, 24894818, 33471991) - |
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Dec 14, 2022 | The frequency of this variant in the general population, 0.00075 (23/30608 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In one study in the Japanese population, this variant was observed in 1/12490 male controls, but not among 7051 female and 53 male breast cancer patients or 11241 female controls (PMID: 30287823 (2018)). The variant was also observed in 1/1358 control individuals but not in 57 cases of melanoma with additional primary cancers (PMID: 29641532 (2018)). In a large scale breast cancer association study, this variant was reported in 2/53461 control individuals but not in 60466 women with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/NBN)). Lastly, the variant was observed in 1/23705 control individuals but not in 1005 cases of pancreatic cancer (PMID: 32980694 (2020)). However since the age of onset and degree of elevated breast cancer risk by the NBN gene is not well defined (PMID: 2625988 (2015)), these reports do not unequivocally support a benign role of this variant. 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. - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Nov 10, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 30, 2023 | 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at