rs1554556880

Variant names:

• chr8-89947822-ACAGAT-A
• rs1554556880
• NM_002485.5:c.1911_1914+1delATCTG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_002485.5(NBN):​c.1911_1914+1delATCTG​(p.Ser638fs) variant causes a frameshift, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NBN NM_002485.5 frameshift, splice_donor, splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2
• Conservation: PhyloP100: 2.40
• 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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-89947822-ACAGAT-A is Pathogenic according to our data. Variant chr8-89947822-ACAGAT-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 492105.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002485.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.1911_1914+1delATCTG	p.Ser638fs	frameshift splice_donor splice_region intron	Exon 12 of 16	NP_002476.2
	NBN	NM_001024688.3		c.1665_1668+1delATCTG	p.Ser556fs	frameshift splice_donor splice_region intron	Exon 13 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.1665_1668+1delATCTG	p.Ser556fs	frameshift splice_donor splice_region intron	Exon 12 of 16	NP_001427308.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.1911_1914+1delATCTG	p.Ser638fs	frameshift splice_donor splice_region intron	Exon 12 of 16	ENSP00000265433.4
	NBN	ENST00000396252.6	TSL:5	n.*1784_*1787+1delATCTG		splice_region non_coding_transcript_exon	Exon 15 of 19	ENSP00000379551.2
	NBN	ENST00000697294.1		n.*1522_*1525+1delATCTG		splice_region non_coding_transcript_exon	Exon 13 of 17	ENSP00000513231.1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Pathogenic:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant results in the deletion of part of exon 12 (c.1911_1914+1del) 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NBN-related conditions. ClinVar contains an entry for this variant (Variation ID: 492105). 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.

Hereditary cancer-predisposing syndrome Uncertain:2

Dec 08, 2020

Color Diagnostics, LLC DBA Color Health

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant deletes 5 nucleotides at the exon 12/intron 12 junction of the NBN gene. This variant may have a significant impact on RNA splicing and may cause the skipping of exon 12, which would result in an in-frame deletion of 23 amino acids. However, this prediction has not been confirmed in published RNA studies. To our knowledge, this variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). While this variant is expected to disrupt the splice donor site of intron 12, the impact on the encoded protein has not been determined. Conflicting classifications have been reported for variants affecting the same splice site (ClinVar variation ID: 492105, 802418). In addition, to our knowledge, there is no experimental or clinical evidence indicating that exon 12 is associated with critical NBN function or NBN-related diseases. The available evidence is insufficient to determine the role of this variant in disease conclusively based on the ACMG guideline (PMID: 30192042). Therefore, this variant is classified as a Variant of Uncertain Significance.

Nov 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1911_1914+1delATCTG intronic variant results from a deletion of 5 nucleotides between positions 1911 and 1914+1 and involves the canonical splice donor site after coding exon 12 of the NBN gene. This nucleotide region is generally well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor 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. The exact functional effect of the altered amino acid sequence is unknown. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.4

Splicing

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

Other links and lift over

dbSNP: rs1554556880; hg19: chr8-90960050;