rs749272832

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_002485.5(NBN):​c.356G>T​(p.Cys119Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,196 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

7
9
3

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 6.00
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NBNNM_002485.5 linkuse as main transcriptc.356G>T p.Cys119Phe missense_variant 4/16 ENST00000265433.8 NP_002476.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NBNENST00000265433.8 linkuse as main transcriptc.356G>T p.Cys119Phe missense_variant 4/161 NM_002485.5 ENSP00000265433 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.85e-7
AC:
1
AN:
1460196
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
726512
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJun 16, 2023In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Studies have shown that this missense change results in activation of a cryptic splice site and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 485929). This variant has not been reported in the literature in individuals affected with NBN-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with phenylalanine, which is neutral and non-polar, at codon 119 of the NBN protein (p.Cys119Phe). RNA analysis indicates that this missense change induces altered splicing and may result in an absent or disrupted protein product. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 20, 2018The p.C119F variant (also known as c.356G>T), located in coding exon 4 of the NBN gene, results from a G to T substitution at nucleotide position 356. The cysteine at codon 119 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.51
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.15
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.43
T;T;.;.
Eigen
Pathogenic
0.83
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Uncertain
0.88
D
LIST_S2
Uncertain
0.91
D;T;D;D
M_CAP
Benign
0.065
D
MetaRNN
Pathogenic
0.95
D;D;D;D
MetaSVM
Benign
-0.52
T
MutationAssessor
Uncertain
2.7
M;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.59
T
PROVEAN
Pathogenic
-7.8
D;D;D;D
REVEL
Uncertain
0.56
Sift
Uncertain
0.0030
D;D;D;D
Sift4G
Pathogenic
0.0
D;D;.;D
Polyphen
1.0
D;.;.;.
Vest4
0.91
MutPred
0.84
Loss of catalytic residue at L120 (P = 0.0087);.;.;.;
MVP
0.82
MPC
0.47
ClinPred
0.99
D
GERP RS
5.8
Varity_R
0.90
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.63
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.63
Position offset: 35

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: rs749272832; hg19: chr8-90993086; API