rs745559078

Variant names:

• chr8-89947853-C-A
• rs745559078
• NM_002485.5:c.1885G>T

Your query was ambiguous. Multiple possible variants found:

• chr8-89947853-C-A
• chr8-89947853-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002485.5(NBN):​c.1885G>T​(p.Asp629Tyr) 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. 15/24 in silico tools predict 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. D629G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.42
• Publications: 2 publications found

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 Gene-Disease associations (from GenCC):

• Nijmegen breakage syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Myriad Women’s Health
• rhabdomyosarcoma

  Inheritance: AR Classification: MODERATE Submitted by: Genomics England PanelApp
• idiopathic aplastic anemia

  Inheritance: AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)
• prostate cancer

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
• hereditary breast carcinoma

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002485.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.1885G>T	p.Asp629Tyr	missense	Exon 12 of 16	NP_002476.2
	NBN	NM_001024688.3		c.1639G>T	p.Asp547Tyr	missense	Exon 13 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.1639G>T	p.Asp547Tyr	missense	Exon 12 of 16	NP_001427308.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.1885G>T	p.Asp629Tyr	missense	Exon 12 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.1885G>T	p.Asp629Tyr	missense	Exon 12 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.1885G>T	p.Asp629Tyr	missense	Exon 12 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1431536 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 712506

African (AFR) AF: 0.00 AC: 0 AN: 32704

American (AMR) AF: 0.00 AC: 0 AN: 43924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25454

East Asian (EAS) AF: 0.00 AC: 0 AN: 39250

South Asian (SAS) AF: 0.00 AC: 0 AN: 84176

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088784

Other (OTH) AF: 0.00 AC: 0 AN: 59120

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:2

Nov 07, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 21, 2016

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with an NBN-related disease. This sequence change replaces aspartic acid with tyrosine at codon 629 of the NBN protein (p.Asp629Tyr). The aspartic acid residue is weakly conserved and there is a large physicochemical difference between aspartic acid and tyrosine. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

not provided Uncertain:1

Aug 02, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); Has not been previously published as pathogenic or benign to our knowledge

Hereditary cancer-predisposing syndrome Uncertain:1

Aug 07, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.D629Y variant (also known as c.1885G>T), located in coding exon 12 of the NBN gene, results from a G to T substitution at nucleotide position 1885. The aspartic acid at codon 629 is replaced by tyrosine, an amino acid with highly dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.78
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.37
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.041
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.012	D
Polyphen		0.68	P
Vest4		0.24
MutPred		0.27		Loss of helix (P = 0.0093)
MVP		0.69
MPC		0.11
ClinPred		0.25	T
GERP RS		3.2
Varity_R		0.079
gMVP		0.14
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.32		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.32		Position offset: -29

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

Other links and lift over

dbSNP: rs745559078; hg19: chr8-90960081;