rs769414

Variant names:

• chr8-89980789-T-C
• rs769414
• NM_002485.5:c.425A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_002485.5(NBN):​c.425A>G​(p.Asn142Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000211 in 1,613,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. N142H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:8 O:1
• Conservation: PhyloP100: 0.114
• Publications: 14 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.05121094).
• BP6: Variant 8-89980789-T-C is Benign according to our data. Variant chr8-89980789-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 127871.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000198 (290/1461318) while in subpopulation MID AF = 0.00746 (43/5764). AF 95% confidence interval is 0.00569. There are 0 homozygotes in GnomAdExome4. There are 155 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.425A>G	p.Asn142Ser	missense	Exon 4 of 16	NP_002476.2
	NBN	NM_001024688.3		c.179A>G	p.Asn60Ser	missense	Exon 5 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.179A>G	p.Asn60Ser	missense	Exon 4 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.425A>G	p.Asn142Ser	missense	Exon 4 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.425A>G	p.Asn142Ser	missense	Exon 4 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.425A>G	p.Asn142Ser	missense	Exon 4 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000167 AC: 42 AN: 251294 AF XY: 0.000184

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000202

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000198 AC: 290 AN: 1461318 Hom.: 0 Cov.: 31 AF XY: 0.000213 AC XY: 155 AN XY: 727018

African (AFR) AF: 0.000359 AC: 12 AN: 33460

American (AMR) AF: 0.000604 AC: 27 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53346

Middle Eastern (MID) AF: 0.00746 AC: 43 AN: 5764

European-Non Finnish (NFE) AF: 0.000151 AC: 168 AN: 1111660

Other (OTH) AF: 0.000629 AC: 38 AN: 60378

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74478

African (AFR) AF: 0.000120 AC: 5 AN: 41568

American (AMR) AF: 0.00124 AC: 19 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68024

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000336

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.000382

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Hereditary cancer-predisposing syndrome (3)
-	1	2	Microcephaly, normal intelligence and immunodeficiency (3)
-	2	1	not provided (3)
-	1	1	not specified (3)
-	1	-	Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency (1)
-	-	1	Hereditary cancer (1)
-	1	-	Malignant tumor of breast (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	12
DANN	Benign	0.91
DEOGEN2	Benign	0.098	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.83	T
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.051	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.43	N
PhyloP100		0.11
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.034
Sift	Benign	0.39	T
Sift4G	Benign	0.84	T
Polyphen		0.13	B
Vest4		0.079
MVP		0.74
MPC		0.057
ClinPred		0.012	T
GERP RS		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.031
gMVP		0.13
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs769414; hg19: chr8-90993017; COSMIC: COSV55377430; COSMIC: COSV55377430;