chr8-89980895-T-C

Variant names:

• chr8-89980895-T-C
• rs587777931
• NM_002485.5:c.321-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002485.5(NBN):​c.321-2A>G variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.000000685 in 1,459,610 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NBN NM_002485.5 splice_acceptor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 6.08
• Publications: 0 publications found

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]

NBN Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• idiopathic aplastic anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 8.6, offset of 41, new splice context is: tgcatgctcttcttgtttAGatg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-89980895-T-C is Pathogenic according to our data. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980895-T-C is described in CliVar as Likely_pathogenic. Clinvar id is 133353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.321-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 15	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.321-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 15	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459610 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726238

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 86220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110868

Other (OTH) AF: 0.00 AC: 0 AN: 60340

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Pathogenic:1

Apr 24, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Disruption of this splice site has been observed in individual(s) with uterine smooth muscle tumor (PMID: 26556299). 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. Studies have shown that disruption of this splice site results in skipping of exon 4 and activation of cryptic splice sites and introduces a premature termination codon (Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 133353). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 3 of the NBN gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Feb 27, 2023

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.321-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 4 in the NBN gene. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as likely pathogenic. -

not specified Other:1

Sep 19, 2013

ITMI

Significance: not provided

Review Status: no classification provided

Collection Method: reference population

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	29
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.85	D
PhyloP100		6.1
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.92		Position offset: -2

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

Other links and lift over

dbSNP: rs587777931; hg19: chr8-90993123;