NM_002485.5:c.493C>A

Variant names:

• chr8-89978311-G-T
• rs776810966
• NM_002485.5:c.493C>A

Variant summary

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

The NM_002485.5(NBN):​c.493C>A​(p.Leu165Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000145 in 1,586,582 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. L165F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000015 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 2.23
• Publications: 0 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 0 ACMG points.

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.493C>A	p.Leu165Ile	missense	Exon 5 of 16	NP_002476.2
	NBN	NM_001024688.3		c.247C>A	p.Leu83Ile	missense	Exon 6 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.247C>A	p.Leu83Ile	missense	Exon 5 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.493C>A	p.Leu165Ile	missense	Exon 5 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.493C>A	p.Leu165Ile	missense	Exon 5 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.493C>A	p.Leu165Ile	missense	Exon 5 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152090 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000153 AC: 22 AN: 1434492 Hom.: 0 Cov.: 28 AF XY: 0.0000182 AC XY: 13 AN XY: 715178

African (AFR) AF: 0.00 AC: 0 AN: 32852

American (AMR) AF: 0.00 AC: 0 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25944

East Asian (EAS) AF: 0.00 AC: 0 AN: 39446

South Asian (SAS) AF: 0.00 AC: 0 AN: 85644

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5718

European-Non Finnish (NFE) AF: 0.0000193 AC: 21 AN: 1087360

Other (OTH) AF: 0.0000168 AC: 1 AN: 59440

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152090 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74284

African (AFR) AF: 0.00 AC: 0 AN: 41416

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10574

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Microcephaly, normal intelligence and immunodeficiency (2)
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	0.20	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.25
Sift	Uncertain	0.0060	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.68
MutPred		0.67		Gain of helix (P = 0.0425)
MVP		0.86
MPC		0.42
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.30
gMVP		0.53
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs776810966; hg19: chr8-90990539;