Genetic Variant NBN:p.Asp629Tyr (chr8-89947853-C-A) – ACMG Classification: Uncertain_significance (2 pts)

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

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.42

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

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

NBN links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

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	A0A0C4DG07
NBN	NM_001440379.1		c.1639G>T	p.Asp547Tyr	missense	Exon 12 of 16	NP_001427308.1

Ensembl Transcripts

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	O60934
NBN	ENST00000697309.1		c.1885G>T	p.Asp629Tyr	missense	Exon 12 of 15	ENSP00000513244.1	A0A8V8TKY5
NBN	ENST00000697293.1		c.1885G>T	p.Asp629Tyr	missense	Exon 12 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1431536

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712506

African (AFR)

AF:

0.00

AC:

AN:

32704

American (AMR)

AF:

0.00

AC:

AN:

43924

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25454

East Asian (EAS)

AF:

0.00

AC:

AN:

39250

South Asian (SAS)

AF:

0.00

AC:

AN:

84176

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52428

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088784

Other (OTH)

AF:

0.00

AC:

AN:

59120

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Microcephaly, normal intelligence and immunodeficiency (2)

Hereditary cancer-predisposing syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.16

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.37

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.67

M_CAP

Benign

0.0098

MetaRNN

Benign

0.22

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

2.4

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

REVEL

Benign

0.041

Sift

Uncertain

0.014

Sift4G

Uncertain

0.012

Polyphen

0.68

Vest4

0.24

MutPred

0.27

Loss of helix (P = 0.0093)

MVP

0.69

MPC

0.11

ClinPred

0.25

GERP RS

3.2

Varity_R

0.079

gMVP

0.14

Mutation Taster

=89/11

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over