rs876658347

Variant names:

• chr8-89953641-A-C
• rs876658347
• NM_002485.5:c.1448T>G

Your query was ambiguous. Multiple possible variants found:

• chr8-89953641-A-C
• chr8-89953641-A-G
• chr8-89953641-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_002485.5(NBN):​c.1448T>G​(p.Ile483Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 1.63

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14869907).
• BP6: Variant 8-89953641-A-C is Benign according to our data. Variant chr8-89953641-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 647409.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.1448T>G	p.Ile483Arg	missense_variant	Exon 11 of 16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.1448T>G	p.Ile483Arg	missense_variant	Exon 11 of 16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:1

Jul 22, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces isoleucine with arginine at codon 483 of the NBN protein (p.Ile483Arg). The isoleucine residue is weakly conserved and there is a moderate physicochemical difference between isoleucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NBN-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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. -

Hereditary cancer-predisposing syndrome Benign:1

Jul 24, 2024

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.096	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.077	T;T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.76	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.3	M;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.055
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.035	D;D
Polyphen		0.88	P;.
Vest4		0.23
MutPred		0.30		Gain of solvent accessibility (P = 0.0171);.;
MVP		0.63
MPC		0.23
ClinPred		0.66	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.25

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

Other links and lift over

dbSNP: rs876658347; hg19: chr8-90965869;