Variant 8-89935609-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PVS1_ModeratePM2PP5

The NM_002485.5(NBN):c.2238C>A(p.Tyr746Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,455,398 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y746Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

NBN
NM_002485.5 stop_gained

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:3

Conservation

PhyloP100: 0.246

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0119 CDS is truncated, and there are 2 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-89935609-G-T is Pathogenic according to our data. Variant chr8-89935609-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 480044.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=3, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5 linkuse as main transcript	c.2238C>A	p.Tyr746Ter	stop_gained	16/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8 linkuse as main transcript	c.2238C>A	p.Tyr746Ter	stop_gained	16/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250384

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135394

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455398

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724230

show subpopulations

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:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Oct 30, 2022	This sequence change creates a premature translational stop signal (p.Tyr746*) in the NBN gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 9 amino acid(s) of the NBN protein. This variant is present in population databases (rs751570713, gnomAD 0.0009%). 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: 480044). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Aplastic anemia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Feb 23, 2024

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 16, 2023

The p.Y746* variant (also known as c.2238C>A), located in coding exon 16 of the NBN gene, results from a C to A substitution at nucleotide position 2238. This changes the amino acid from a tyrosine to a stop codon within coding exon 16. One study detected this mutation in 0/3030 pancreatic cancer cases and 1/123136 population controls (Hu C et al. JAMA, 2018 06;319:2401-2409). This stop codon occurs at the 3' terminus of NBN, is not expected to trigger nonsense-mediated mRNA decay, and removes only the last 9 amino acids of the protein. However, the truncation occurs in an ATM binding domain, and upstream of a nuclear localization signal. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Apr 10, 2017

This variant is denoted NBN c.2238C>A at the cDNA level and p.Tyr746Ter (Y746X) at the protein level. The substitution creates a nonsense variant, which changes a Tyrosine to a premature stop codon (TAC>TAA). This variant has not, to our knowledge, been reported in the literature. NBN Tyr746Ter results in the loss of 9 amino acids at the end of the protein, which might affect normal function. However, due to the location of the newly created nonsense codon in the last exon, the transcript is not expected to undergo nonsense-mediated decay and could therefore encode a truncated protein that retains some normal function. The deleted residues are located in the region of interaction with ATM (Damiola 2014). NBN Tyr746Ter was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Based on currently available evidence, it is unclear whether NBN Tyr746Ter is a pathogenic or benign variant. We consider it to be a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Uncertain

0.25

Eigen_PC

Benign

0.078

FATHMM_MKL

Uncertain

0.87

MutationTaster

Benign

1.0

D;D

Vest4

0.74

GERP RS

0.41

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over