rs375862750
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Variant summary
Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBP6
The NM_002485.5(NBN):c.1124+6G>T variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000632 in 1,613,326 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 0.00012 ( 1 hom., cov: 32)
Exomes 𝑓: 0.000057 ( 0 hom. )
Consequence
NBN
NM_002485.5 splice_donor_region, intron
NM_002485.5 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.00009772
2
Clinical Significance
Conservation
PhyloP100: -1.09
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 Likely_benign. Variant got -5 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.6).
BP6
?
Variant 8-89958719-C-A is Benign according to our data. Variant chr8-89958719-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138426.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=6, Benign=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.1124+6G>T | splice_donor_region_variant, intron_variant | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.1124+6G>T | splice_donor_region_variant, intron_variant | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000125 AC: 19AN: 152136Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000115 AC: 29AN: 251304Hom.: 0 AF XY: 0.000125 AC XY: 17AN XY: 135822
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GnomAD4 exome AF: 0.0000568 AC: 83AN: 1461190Hom.: 0 Cov.: 32 AF XY: 0.0000564 AC XY: 41AN XY: 726950
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:4Benign:8
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Uncertain:2Benign:2
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 10, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Feb 21, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Jan 04, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Mar 05, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 09, 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. - |
not specified Uncertain:1Benign:1
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2014 | 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 23, 2019 | Variant summary: NBN c.1124+6G>T alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00012 in 251304 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.00012 vs 0.0025), allowing no conclusion about variant significance. c.1124+6G>T has been reported in the literature in individuals affected with breast cancer and colorectal cancer (Tung_2014, Yurgelun_2017). These reports do not provide unequivocal conclusions about association of the variant with Nijmegen Breakage Syndrome. A co-occurrence with a pathogenic variant has been reported (BRCA1 c.4357+1G>A; LabCorp), providing supporting evidence for a benign role. 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. Two labs classified the variant as likely benign while two classified as VUS. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant. - |
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 20, 2017 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 20, 2021 | - - |
Malignant tumor of breast Benign:1
Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NBN c.1124+6G>T variant was not identified in the literature nor was it identified in Cosmic, LOVD 3.0, or Zhejiang Colon Cancer Databases. The variant was identified in dbSNP (ID: rs375862750) “With Uncertain significance allele”, ClinVar (classified with conflicting interpretations of pathogenicity; submitters: benign by GeneDx and uncertain significance by Invitae), and Clinvitae (2x). The variant was identified in control databases in 30 of 277024 chromosomes at a frequency of 0.0001 increasing the likelihood that this may be a low frequency benign variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). The c.1124+6G>T variant is located in the 5' splice region but does not affect the invariant +1 and +2 positions. However, positions +3 to +6 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. - |
Computational scores
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at