rs1554554265

Variant names:

• chr8-89937066-G-A
• rs1554554265
• NM_002485.5:c.2194C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_002485.5(NBN):​c.2194C>T​(p.Gln732*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. Q732Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NBN NM_002485.5 stop_gained
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 3.54
• 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: Likely_pathogenic. The variant received 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 8-89937066-G-A is Pathogenic according to our data. Variant chr8-89937066-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 461545.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.2194C>T	p.Gln732*	stop_gained	Exon 15 of 16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.2194C>T	p.Gln732*	stop_gained	Exon 15 of 16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency Pathogenic:1

May 11, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly, normal intelligence and immunodeficiency Pathogenic:1

Dec 08, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. This variant disrupts the ATM interaction domain of the NBN protein (PMID: 24894818, 21035407), which is important for activating ATM in the double-strand break repair pathway (PMID: 15964794, 15048089). While functional studies have not been performed to directly test the effect of this variant on NBN protein function, this suggests that disruption of this region of the protein is causative of disease. ClinVar contains an entry for this variant (Variation ID: 461545). 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 creates a premature translational stop signal (p.Gln732*) in the NBN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 23 amino acid(s) of the NBN protein. -

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q732* variant (also known as c.2194C>T), located in coding exon 15 of the NBN gene, results from a C to T substitution at nucleotide position 2194. This changes the amino acid from a glutamine to a stop codon within coding exon 15. This alteration occurs at the 3' terminus of theNBN gene, is not expected to trigger nonsense-mediated mRNAdecay, and only impacts the last 23 amino acids of the protein. This alteration is expected to disrupt the C-terminus of the NBN protein which has been shown to be necessary for binding to the ATM protein (Falck J et al. Nature 2005 Mar;434:605-11); however, the exact functional impact of this particular alteration is unknown at this time. 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_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	44
DANN	Uncertain	0.99
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.91	D
PhyloP100		3.5
Vest4		0.86
GERP RS		3.5
Mutation Taster		=6/194	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.21		Position offset: 9

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

Other links and lift over

dbSNP: rs1554554265; hg19: chr8-90949294;