chr8-89971262-T-A

Variant names:

• chr8-89971262-T-A
• rs730881845
• NM_002485.5:c.613A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_002485.5(NBN):​c.613A>T​(p.Ile205Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,460,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I205T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.05
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.37320372).

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.613A>T	p.Ile205Phe	missense	Exon 6 of 16	NP_002476.2
	NBN	NM_001024688.3		c.367A>T	p.Ile123Phe	missense	Exon 7 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.367A>T	p.Ile123Phe	missense	Exon 6 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.613A>T	p.Ile205Phe	missense	Exon 6 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.613A>T	p.Ile205Phe	missense	Exon 6 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.613A>T	p.Ile205Phe	missense	Exon 6 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460734 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726702

African (AFR) AF: 0.00 AC: 0 AN: 33416

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39588

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53300

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111354

Other (OTH) AF: 0.00 AC: 0 AN: 60332

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.37	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Uncertain	2.9	M
PhyloP100		4.1
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.26
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.026	D
Polyphen		1.0	D
Vest4		0.65
MutPred		0.17		Loss of methylation at K208 (P = 0.1388)
MVP		0.90
MPC		0.49
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.31
gMVP		0.52
Mutation Taster		=66/34	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: rs730881845; hg19: chr8-90983490;