rs1554553897

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000265433.8(NBN):​c.2235-3C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 32)

Consequence

NBN
ENST00000265433.8 splice_region, splice_polypyrimidine_tract, intron

Scores

2
Splicing: ADA: 0.8185
2

Clinical Significance

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

Conservation

PhyloP100: 3.39
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.22).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NBNNM_002485.5 linkuse as main transcriptc.2235-3C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant ENST00000265433.8 NP_002476.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NBNENST00000265433.8 linkuse as main transcriptc.2235-3C>T splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant 1 NM_002485.5 ENSP00000265433 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
29
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:1
Uncertain significance, criteria provided, single submitterclinical testingGenome-Nilou LabNov 07, 2021- -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingQuest Diagnostics Nichols Institute San Juan CapistranoFeb 27, 2018- -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsSep 20, 2022The c.2235-3C>T intronic variant results from a C to T substitution 3 nucleotides upstream from coding exon 16 in the NBN gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will not have any significant effect on splicing. 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
BayesDel_noAF
Benign
-0.22
CADD
Benign
18
DANN
Benign
0.92

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.82
dbscSNV1_RF
Benign
0.32
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: rs1554553897; hg19: chr8-90947843; API