rs147626427

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

Scores

1
11
7

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:6

Conservation

PhyloP100: 4.29
Variant links:
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]

Genome browser will be placed here

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
NBNNM_002485.5 linkuse as main transcriptc.788T>C p.Phe263Ser missense_variant 7/16 ENST00000265433.8 NP_002476.2 O60934

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NBNENST00000265433.8 linkuse as main transcriptc.788T>C p.Phe263Ser missense_variant 7/161 NM_002485.5 ENSP00000265433.4 O60934

Frequencies

GnomAD3 genomes
AF:
0.000565
AC:
86
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00203
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000131
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000167
AC:
42
AN:
251296
Hom.:
0
AF XY:
0.000177
AC XY:
24
AN XY:
135810
show subpopulations
Gnomad AFR exome
AF:
0.00246
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000568
AC:
83
AN:
1461684
Hom.:
0
Cov.:
31
AF XY:
0.0000605
AC XY:
44
AN XY:
727146
show subpopulations
Gnomad4 AFR exome
AF:
0.00230
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.000565
AC:
86
AN:
152330
Hom.:
0
Cov.:
32
AF XY:
0.000550
AC XY:
41
AN XY:
74490
show subpopulations
Gnomad4 AFR
AF:
0.00202
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000237
Hom.:
0
Bravo
AF:
0.000740
ESP6500AA
AF:
0.00182
AC:
8
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.000222
AC:
27

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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJan 18, 2019Variant 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 submitterclinical testingGenetic Services Laboratory, University of ChicagoApr 27, 2016- -
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoDec 09, 2022- -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxNov 09, 2023In 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 submittercurationSema4, Sema4Dec 21, 2021- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 13, 2021This 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 submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 29, 2024- -
NBN-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesSep 21, 2024The 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 submitterclinical testingMendelicsJan 23, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.55
BayesDel_addAF
Benign
-0.31
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.32
T;T
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.49
FATHMM_MKL
Uncertain
0.87
D
LIST_S2
Benign
0.71
T;T
M_CAP
Uncertain
0.10
D
MetaRNN
Benign
0.16
T;T
MetaSVM
Uncertain
-0.12
T
MutationAssessor
Uncertain
2.3
M;.
PrimateAI
Benign
0.48
T
PROVEAN
Uncertain
-3.3
D;D
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0040
D;D
Sift4G
Uncertain
0.0040
D;D
Polyphen
1.0
D;.
Vest4
0.78
MVP
0.82
MPC
0.27
ClinPred
0.097
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.56
gMVP
0.79

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs147626427; hg19: chr8-90982700; API