Genetic Variant NBN:p.Leu574Ile (chr8-89953369-A-T) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002485.5(NBN):c.1720T>A(p.Leu574Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00087 in 1,613,254 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L574V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00091 ( 3 hom. )

Consequence

NBN
NM_002485.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:17O:2

Conservation

PhyloP100: -0.197

Publications

9 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: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062530637).

BP6

Variant 8-89953369-A-T is Benign according to our data. Variant chr8-89953369-A-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127861.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000911 (1332/1461374) while in subpopulation NFE AF = 0.00105 (1162/1111782). AF 95% confidence interval is 0.000995. There are 3 homozygotes in GnomAdExome4. There are 641 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR,AD gene

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.1720T>A	p.Leu574Ile	missense	Exon 11 of 16	NP_002476.2
NBN	NM_001024688.3		c.1474T>A	p.Leu492Ile	missense	Exon 12 of 17	NP_001019859.1	A0A0C4DG07
NBN	NM_001440379.1		c.1474T>A	p.Leu492Ile	missense	Exon 11 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.1720T>A	p.Leu574Ile	missense	Exon 11 of 16	ENSP00000265433.4	O60934
NBN	ENST00000697309.1		c.1720T>A	p.Leu574Ile	missense	Exon 11 of 15	ENSP00000513244.1	A0A8V8TKY5
NBN	ENST00000697293.1		c.1720T>A	p.Leu574Ile	missense	Exon 11 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes

AF:

0.000474

AC:

AN:

151762

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00104

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000796

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.000721

AC:

181

AN:

251186

AF XY:

0.000655

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000867

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00153

Gnomad NFE exome

AF:

0.00109

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000911

AC:

1332

AN:

1461374

Hom.:

Cov.:

AF XY:

0.000882

AC XY:

641

AN XY:

727014

show subpopulations

African (AFR)

AF:

0.000120

AC:

AN:

33466

American (AMR)

AF:

0.0000671

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39660

South Asian (SAS)

AF:

0.000487

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00148

AC:

AN:

53228

Middle Eastern (MID)

AF:

0.000867

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00105

AC:

1162

AN:

1111782

Other (OTH)

AF:

0.000613

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

144

217

289

361

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

176

220

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000474

AC:

AN:

151880

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

AN XY:

74234

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.000208

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00104

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000796

AC:

AN:

67866

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000576

Hom.:

Bravo

AF:

0.000427

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000930

AC:

ExAC

AF:

0.000758

AC:

EpiCase

AF:

0.000763

EpiControl

AF:

0.00113

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (9)

Microcephaly, normal intelligence and immunodeficiency (4)

Hereditary cancer-predisposing syndrome (3)

Malignant tumor of breast (1)

not specified (2)

Acute lymphoid leukemia;C0027672:Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.57

CADD

Benign

7.1

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.23

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.75

M_CAP

Benign

0.013

MetaRNN

Benign

0.0063

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

-0.20

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.36

REVEL

Benign

0.053

Sift

Benign

0.41

Sift4G

Benign

0.45

Polyphen

0.085

Vest4

0.21

MVP

0.67

MPC

0.091

ClinPred

0.011

GERP RS

1.0

PromoterAI

0.0024

Neutral

(source)

Varity_R

0.026

gMVP

0.043

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over