8-89981505-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002485.5(NBN):c.190C>A(p.Pro64Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,622 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P64L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.190C>A	p.Pro64Thr	missense_variant	3/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.190C>A	p.Pro64Thr	missense_variant	3/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460622 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726724

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2023

The p.P64T variant (also known as c.190C>A), located in coding exon 3 of the NBN gene, results from a C to A substitution at nucleotide position 190. The proline at codon 64 is replaced by threonine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;.
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	0.99	D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.1	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.038	D;D
Polyphen		1.0	D;.
Vest4		0.53
MutPred		0.58		Gain of sheet (P = 0.0101);Gain of sheet (P = 0.0101);
MVP		0.97
MPC		0.20
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.42
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs267602038; hg19: chr8-90993733; COSMIC: COSV105039059; COSMIC: COSV105039059;