rs746422391

Positions:

chr8-89984560-A-G

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1PM2PP5

The NM_002485.5(NBN):c.2T>C(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.00000342 in 1,460,798 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).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

NBN
NM_002485.5 start_lost

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2

Conservation

PhyloP100: 4.30

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 Pathogenic. Variant got 11 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 8-89984560-A-G is Pathogenic according to our data. Variant chr8-89984560-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421151.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=2}. Variant chr8-89984560-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NBN	NM_002485.5 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/16	ENST00000265433.8	NP_002476.2
NBN	XM_011517046.2 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/11		XP_011515348.1
NBN	XM_047421796.1 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/10		XP_047277752.1
NBN	NM_001024688.3 linkuse as main transcript	c.-295T>C		5_prime_UTR_variant	1/17		NP_001019859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8 linkuse as main transcript	c.2T>C	p.Met1?	start_lost	1/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000408

AC:

AN:

245228

Hom.:

AF XY:

0.00000747

AC XY:

AN XY:

133906

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:

0.00000911

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1460798

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

726774

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:

0.00000450

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000825

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 28, 2022	This sequence change affects the initiator methionine of the NBN mRNA. The next in-frame methionine is located at codon 83. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with rectal adenocarcinoma (PMID: 29625052). ClinVar contains an entry for this variant (Variation ID: 421151). This variant at the initiator codon is expected to affect translation initiation. Rescue of translation at the next in-frame methionine at codon 83 is expected to disrupt the forkhead-associated (FHA) domain (PMID: 9590180, 26315354), which facilitates DNA repair responses (PMID: 11062235, 19804755, 12433983). However, functional studies have not been performed for this variant. 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 31, 2021

Initiation codon variant in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (Lek et al., 2016); Reported in an individual with rectal cancer (Huang 2018); This variant is associated with the following publications: (PMID: 29625052) -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2022

The p.M1? variant (also known as c.2T>C) is located in coding exon 1 of the NBN gene and results from a T to C substitution at nucleotide position 2. This alters the methionine residue at the initiation codon (ATG). There is an in-frame methionine 83 amino acids downstream, which may act as an alternative initiation codon and result in an N-terminal truncation; however, direct evidence is unavailable. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is highly conserved in available vertebrate species. Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Pathogenic

0.27

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.51

D;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.11

LIST_S2

Uncertain

0.90

D;D

M_CAP

Pathogenic

0.87

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Uncertain

0.088

MutationTaster

Benign

1.0

PROVEAN

Uncertain

-3.8

D;D

REVEL

Pathogenic

0.70

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.94

MutPred

0.98

Loss of stability (P = 0.0179);Loss of stability (P = 0.0179);

MVP

0.87

ClinPred

1.0

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.93

gMVP

0.87

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