rs864309670

Positions:

• chr8-89970517-T-TCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002485.5(NBN):​c.742_743insGG​(p.Glu248GlyfsTer5) variant causes a frameshift 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NBN NM_002485.5 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6 O:1
• Conservation: PhyloP100: -0.0510

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 Pathogenic. Variant got 18 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 8-89970517-T-TCC is Pathogenic according to our data. Variant chr8-89970517-T-TCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6949.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.742_743insGG	p.Glu248GlyfsTer5	frameshift_variant	7/16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.742_743insGG	p.Glu248GlyfsTer5	frameshift_variant	7/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Pathogenic:4 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2006	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 07, 2021	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6949). This premature translational stop signal has been observed in individual(s) with Nijmegen breakage syndrome (PMID: 2625251, 3802554, 16415040). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Glu248Glyfs*5) in the NBN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NBN are known to be pathogenic (PMID: 9590180, 16415040). -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jun 13, 2022	Variant summary: NBN c.741_742dupGG (p.Glu248GlyfsX5) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. Experimental evidence has shown that this variant affects mRNA splicing: recovered transcripts from a homozygous patient were missing exons 6-7 (Varon_2006). Complementation experiments using mouse cells deficient in NBN showed that this alternative transcript was able to rescue some cell survival (Varon_2006). The variant was absent in 251058 control chromosomes (gnomAD). c.741_742dupGG has been reported in the literature in at least one homozygous individual affected with Nijmegen Breakage Syndrome (Di Masi_2006). These data indicate that the variant may be associated with disease. Five ClinVar submitters have assessed the variant since 2014: one classified the variant as likely pathogenic and four as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 18, 2021

Published functional studies demonstrate a damaging effect showing an alternatively spliced transcript involving an in-frame deletion of exon 6 and 7 and also the absence of full length NBN protein by immunoprecipitation (Varon 2006, Salewsky 2016); Not observed at significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21436738, 16415040, 22373003, 3802554, 26265251) -

Hereditary cancer-predisposing syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 24, 2023

The c.741_742dupGG variant, located in coding exon 7 of the NBN gene, results from a duplication of GG at nucleotide position 741, causing a translational frameshift with a predicted alternate stop codon (p.E248Gfs*5). This alteration has been reported in the homozygous state in an individual affected with a mild Nijmegen breakage syndrome phenotype (Varon R et al. Hum. Mol. Genet., 2006 Mar;15:679-89). Functional studies have shown that this variant produces an abnormal in frame transcript lacking exons 6 and 7 that can produce a protein with partial functionality (Varon R et al. Hum. Mol. Genet., 2006 Mar;15:679-89). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs864309670; hg19: chr8-90982745;