rs574673404
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Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_002485.5(NBN):c.37+1G>A variant causes a splice donor change. The variant allele was found at a frequency of 0.0000031 in 1,612,984 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NBN
NM_002485.5 splice_donor
NM_002485.5 splice_donor
Scores
2
3
2
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 3.61
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 Pathogenic. Variant got 22 ACMG points.
PVS1
?
Splicing variant, LoF is a know mechanism of disease,
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 8-89984524-C-T is Pathogenic according to our data. Variant chr8-89984524-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 186314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89984524-C-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NBN | NM_002485.5 | c.37+1G>A | splice_donor_variant | ENST00000265433.8 | |||
NBN | NM_001024688.3 | c.-260+1G>A | splice_donor_variant | ||||
NBN | XM_011517046.2 | c.37+1G>A | splice_donor_variant | ||||
NBN | XM_047421796.1 | c.37+1G>A | splice_donor_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NBN | ENST00000265433.8 | c.37+1G>A | splice_donor_variant | 1 | NM_002485.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152268Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000815 AC: 2AN: 245328Hom.: 0 AF XY: 0.00000747 AC XY: 1AN XY: 133894
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GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460598Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1AN XY: 726658
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GnomAD4 genome ? AF: 0.0000262 AC: 4AN: 152386Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74520
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 04, 2023 | This sequence change affects a donor splice site in intron 1 of the NBN gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). This variant is present in population databases (rs574673404, gnomAD 0.004%). Disruption of this splice site has been observed in individual(s) with endometrial, breast, and/or ovarian cancer (PMID: 30651582, 34284872, 34994648). ClinVar contains an entry for this variant (Variation ID: 186314). RNA analysis provides insufficient evidence to determine the effect of this variant on NBN splicing (Invitae). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Mar 01, 2018 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 12, 2023 | Variant summary: NBN c.37+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes the canonical 5' splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.2e-06 in 245328 control chromosomes (gnomAD). c.37+1G>A has been reported in the literature in individuals affected with various types of cancer (example: Tsaousis_2019, Levine_2021, Yang_2022 and Krivokuca_2022). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 34284872, 34994648, 31159747, 36451132). Eleven clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 20, 2022 | Canonical splice site variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with ovarian or kidney cancer (Huang 2018, Krivokuca 2019); This variant is associated with the following publications: (PMID: 29625052, 9590180, 16415040, 31159747, 31589614, 32295079, 30651582, 32906206) - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 18, 2019 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneKor MSA | Jan 01, 2020 | This variation occurs 1 base after exon 1 of the NBN gene. This position is highly conserved in the human and other genomes and is crucial in mRNA processing. This mutation is expected to result in incorrect splicing, alteration in the reading frame and a truncated protein. The mutation database ClinVar contains entries for this variant (Variation ID: 186314) - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 10, 2023 | The c.37+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 1 of the NBN gene. This alteration has been reported in 1/1197 individuals from Greece, Romania, and Turkey undergoing evaluation for inherited cancer predisposition (Tsaousis GN et al. BMC Cancer, 2019 Jun;19:535) and in 1/131 high grade serous ovarian cancer patients from Serbia (Krivokuca A et al. J. Hum. Genet., 2019 Apr;64:281-290). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site and may result in the creation or strengthening of a novel splice donor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay; however, direct evidence is insufficient at this time (Ambry internal data). As such, this alteration is classified as likely pathogenic. - |
Likely pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 11, 2021 | - - |
Aplastic anemia Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 01, 2024 | - - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
Breast-ovarian cancer, familial, susceptibility to, 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Department of Molecular Diagnostics, Institute of Oncology Ljubljana | Apr 02, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
N
MutationTaster
Benign
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DG_spliceai
Position offset: -37
DS_DL_spliceai
Position offset: 1
Find out detailed SpliceAI scores and Pangolin per-transcript scores at