rs141443872
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6BP7
The NM_002485.5(NBN):c.804G>T(p.Thr268Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,613,884 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NBN
NM_002485.5 synonymous
NM_002485.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -1.42
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 -4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
BP6
Variant 8-89970456-C-A is Benign according to our data. Variant chr8-89970456-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 461581.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}.
BP7
Synonymous conserved (PhyloP=-1.42 with no splicing effect.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461708Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727152
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GnomAD4 genome 0.00000657 AC: 1AN: 152176Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74342
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:3
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Microcephaly, normal intelligence and immunodeficiency Benign:2
| Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 18, 2023 | - - |
| Likely benign, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The NBN p.Thr268Thr variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs141443872) as “With Likely benign allele” and ClinVar (classified as likely benign by Invitae). The variant was identified in control databases in 17 of 277068 chromosomes at a frequency of 0.00006 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: African in 12 of 24032 chromosomes (freq: 0.0005), South Asian in 2 of 30782 chromosomes (freq: 0.000065), Latino in 2 of 34384 chromosomes (freq: 0.00006) and European in 1 of 126614 chromosomes (freq: 0.000008), while the variant was not observed in the Ashkenazi Jewish, East Asian or Finnish populations. The p.Thr268Thr variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. This variant was identified by our laboratory in a patient with a co-occurring, pathogenic ATM variant (c.1564_1565del, p.Glu522Ilefs*43), decreasing the likelihood that this variant has clinical significance. 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 Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 18, 2024 | The c.804G>T variant (also known as p.T268T), located in coding exon 7 of the NBN gene, results from a G to T substitution at nucleotide position 804. This nucleotide substitution does not change the amino acid at codon 268. This nucleotide position is poorly conserved in available vertebrate species. In silico splice site analysis for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
| Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 28, 2021 | - - |
Computational scores
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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