8-89947893-C-T

Variant names:

• chr8-89947893-C-T
• rs61753717
• NM_002485.5:c.1846-1G>A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_Moderate PM2 PP5

The NM_002485.5(NBN):​c.1846-1G>A variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,384,904 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NBN NM_002485.5 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 1.71

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.030463576 fraction of the gene. Cryptic splice site detected, with MaxEntScore 4.7, offset of -23, new splice context is: tttattactcctatgaacAGtat. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-89947893-C-T is Pathogenic according to our data. Variant chr8-89947893-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 371415.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}. Variant chr8-89947893-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.1846-1G>A		splice_acceptor_variant, intron_variant	Intron 11 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.1846-1G>A		splice_acceptor_variant, intron_variant	Intron 11 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1384904 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 689506

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 9.51e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Pathogenic:2

Jul 26, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 371415). 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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 affects an acceptor splice site in intron 11 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). -

Sep 21, 2016

Counsyl

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Gastric cancer Pathogenic:1

Jul 01, 2021

Laboratory for Genotyping Development, RIKEN

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Aplastic anemia Uncertain:1

Mar 19, 2024

Baylor Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary cancer-predisposing syndrome Uncertain:1

Oct 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1846-1G>A intronic variant results from a G to A substitution one nucleotide upstream from coding exon 12 of the NBN gene. This alteration was not observed in unselected male breast cancer patients and was observed with an allele frequency of 0.0001 in 12,490 male controls of Japanese ancestry (Momozawa Y et al. Nat Commun, 2018 10;9:4083). This variant was reported in 1/60,466 breast cancer cases and in 1/53,461 controls (Dorling et al. N Engl J Med. 2021 02;384:428-439). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). The resulting transcript is predicted to be in-frame and is not expected to trigger nonsense-mediated mRNA decay; however, direct evidence is unavailable. The exact functional effect of the altered amino acid sequence is unknown. This nucleotide position is highly conserved in available vertebrate species. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Uncertain	0.80	D
GERP RS		4.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.95
SpliceAI score (max)		0.67		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.67		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs61753717; hg19: chr8-90960121;