rs1060503457

Positions:

• chr8-89978265-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002485.5(NBN):​c.539T>G​(p.Phe180Cys) 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. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F180L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.23

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41051376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.539T>G	p.Phe180Cys	missense_variant	5/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.539T>G	p.Phe180Cys	missense_variant	5/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 18, 2021

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. 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"). ClinVar contains an entry for this variant (Variation ID: 411744). This variant has not been reported in the literature in individuals affected with NBN-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with cysteine at codon 180 of the NBN protein (p.Phe180Cys). The phenylalanine residue is weakly conserved and there is a large physicochemical difference between phenylalanine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.80	T;T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	0.90	D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.1	D;D;D
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		1.0	D;.;.
Vest4		0.51
MutPred		0.49		Loss of helix (P = 0.0093);.;.;
MVP		0.67
MPC		0.10
ClinPred		0.98	D
GERP RS		6.0
Varity_R		0.38
gMVP		0.59

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: rs1060503457; hg19: chr8-90990493;