rs577706448
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1
The NM_002485.5(NBN):c.1914+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000127 in 1,517,332 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: 0.00012 ( 1 hom. )
Consequence
NBN
NM_002485.5 intron
NM_002485.5 intron
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.0410
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 -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.9).
BP6
?
Variant 8-89947814-C-T is Benign according to our data. Variant chr8-89947814-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 138428.We mark this variant Likely_benign, oryginal submissions are: {Benign=4, Uncertain_significance=1, Likely_benign=4}. Variant chr8-89947814-C-T is described in Lovd as [Likely_benign].
BS1
?
Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000124 (169/1365202) while in subpopulation SAS AF= 0.00127 (104/81896). AF 95% confidence interval is 0.00107. There are 1 homozygotes in gnomad4_exome. There are 109 alleles in male gnomad4_exome subpopulation. Median coverage is 22. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.1914+10G>A | intron_variant | ENST00000265433.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.1914+10G>A | intron_variant | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000151 AC: 23AN: 152012Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000267 AC: 59AN: 220710Hom.: 1 AF XY: 0.000319 AC XY: 38AN XY: 119088
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GnomAD4 exome AF: 0.000124 AC: 169AN: 1365202Hom.: 1 Cov.: 22 AF XY: 0.000160 AC XY: 109AN XY: 681646
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:12
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Counsyl | Oct 11, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Nov 11, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | - - |
not provided Benign:4
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Mar 19, 2019 | - - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 10, 2017 | - - |
not specified Uncertain:1Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 23, 2020 | Variant summary: NBN c.1914+10G>A 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. 4/4 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 0.00027 in 220710 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not significantly higher than expected for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.00027 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1914+10G>A in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as benign/likely benign. 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 | Dec 05, 2014 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Feb 25, 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. - |
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.1914+10G>A variant was not identified in the literature. The variant was identified in dbSNP (rs577706448) as “with other allele”, ClinVar (classified as likely benign by Color, Counsyl and Prevention Genetics; as benign by Invitae and GeneDx and as uncertain significance by University of Chicago) and LOVD 3.0 (observed 1x). The variant was identified in control databases in 59 of 220,710 chromosomes (1 homozygous) at a frequency of 0.0003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: South Asian in 34 of 27,638 chromosomes (freq: 0.001), Latino in 15 of 32,818 chromosomes (freq: 0.0005), Other in 1 of 5498 chromosomes (freq: 0.0002), African in 1 of 13,392 chromosomes (freq: 0.00008), European in 7 of 94,896 chromosomes (freq: 0.00007) and Finnish in 1 of 20,126 chromosomes (freq: 0.00005), while the variant was not observed in the Ashkenazi Jewish or East Asian populations. The variant occurs at a non-highly conserved nucleotide outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) 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. - |
Hereditary cancer-predisposing syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 29, 2015 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
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Benign
Dann
Benign
Splicing
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at