rs769418

Variant names:

• chr8-89970575-C-T
• rs769418
• NM_002485.5:c.703-18G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002485.5(NBN):​c.703-18G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,607,802 control chromosomes in the GnomAD database, including 2,898 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.043 (274 hom., cov: 32)
  • Exomes 𝑓: 0.042 (2624 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.76
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 8-89970575-C-T is Benign according to our data. Variant chr8-89970575-C-T is described in ClinVar as Benign. ClinVar VariationId is 258770.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.178 is higher than 0.05.

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.703-18G>A		intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.457-18G>A		intron	N/A	NP_001019859.1
	NBN	NM_001440379.1		c.457-18G>A		intron	N/A	NP_001427308.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.703-18G>A		intron	N/A	ENSP00000265433.4
	NBN	ENST00000697309.1		c.703-18G>A		intron	N/A	ENSP00000513244.1
	NBN	ENST00000697293.1		c.703-18G>A		intron	N/A	ENSP00000513230.1

Frequencies

GnomAD3 genomes AF: 0.0425 AC: 6471 AN: 152138 Hom.: 273 Cov.: 32

Gnomad AFR AF: 0.00997

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.0159

Gnomad EAS AF: 0.187

Gnomad SAS AF: 0.0732

Gnomad FIN AF: 0.0778

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0304

Gnomad OTH AF: 0.0412

GnomAD2 exomes AF: 0.0716 AC: 17795 AN: 248624 AF XY: 0.0663

Gnomad AFR exome AF: 0.00914

Gnomad AMR exome AF: 0.196

Gnomad ASJ exome AF: 0.0201

Gnomad EAS exome AF: 0.182

Gnomad FIN exome AF: 0.0762

Gnomad NFE exome AF: 0.0292

Gnomad OTH exome AF: 0.0573

GnomAD4 exome AF: 0.0422 AC: 61470 AN: 1455546 Hom.: 2624 Cov.: 31 AF XY: 0.0425 AC XY: 30768 AN XY: 724406

African (AFR) AF: 0.00807 AC: 269 AN: 33324

American (AMR) AF: 0.185 AC: 8257 AN: 44644

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 511 AN: 26086

East Asian (EAS) AF: 0.193 AC: 7649 AN: 39602

South Asian (SAS) AF: 0.0686 AC: 5908 AN: 86070

European-Finnish (FIN) AF: 0.0725 AC: 3860 AN: 53266

Middle Eastern (MID) AF: 0.0167 AC: 96 AN: 5754

European-Non Finnish (NFE) AF: 0.0292 AC: 32336 AN: 1106578

Other (OTH) AF: 0.0429 AC: 2584 AN: 60222

GnomAD4 genome AF: 0.0425 AC: 6478 AN: 152256 Hom.: 274 Cov.: 32 AF XY: 0.0477 AC XY: 3551 AN XY: 74442

African (AFR) AF: 0.00991 AC: 412 AN: 41554

American (AMR) AF: 0.110 AC: 1687 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0159 AC: 55 AN: 3470

East Asian (EAS) AF: 0.188 AC: 971 AN: 5178

South Asian (SAS) AF: 0.0737 AC: 356 AN: 4830

European-Finnish (FIN) AF: 0.0778 AC: 825 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0304 AC: 2067 AN: 68016

Other (OTH) AF: 0.0412 AC: 87 AN: 2110

Alfa AF: 0.0332 Hom.: 27

Bravo AF: 0.0465

Asia WGS AF: 0.136 AC: 472 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Microcephaly, normal intelligence and immunodeficiency (3)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	Acute lymphoid leukemia (1)
-	-	1	Hereditary breast ovarian cancer syndrome (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.81
DANN	Benign	0.51
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs769418; hg19: chr8-90982803; COSMIC: COSV55371926;