rs1063053

Variant names:

• chr8-89935309-C-T
• rs1063053
• NM_002485.5:c.*273G>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.*273G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.314 in 381,352 control chromosomes in the GnomAD database, including 19,295 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7150 hom., cov: 32)
  • Exomes 𝑓: 0.32 (12145 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.123
• Publications: 26 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=-0.83).
• BP6: Variant 8-89935309-C-T is Benign according to our data. Variant chr8-89935309-C-T is described in ClinVar as Benign. ClinVar VariationId is 363909.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.391 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.*273G>A		3_prime_UTR	Exon 16 of 16	NP_002476.2
	NBN	NM_001024688.3		c.*273G>A		3_prime_UTR	Exon 17 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.*273G>A		3_prime_UTR	Exon 16 of 16	NP_001427308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.*273G>A		3_prime_UTR	Exon 16 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.*139G>A		3_prime_UTR	Exon 15 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.*273G>A		3_prime_UTR	Exon 17 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes AF: 0.305 AC: 46343 AN: 151726 Hom.: 7143 Cov.: 32

Gnomad AFR AF: 0.258

Gnomad AMI AF: 0.337

Gnomad AMR AF: 0.288

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.319

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.263

Gnomad NFE AF: 0.332

Gnomad OTH AF: 0.300

GnomAD4 exome AF: 0.319 AC: 73323 AN: 229508 Hom.: 12145 Cov.: 3 AF XY: 0.318 AC XY: 37880 AN XY: 119076

African (AFR) AF: 0.252 AC: 1868 AN: 7402

American (AMR) AF: 0.290 AC: 2584 AN: 8922

Ashkenazi Jewish (ASJ) AF: 0.263 AC: 2254 AN: 8558

East Asian (EAS) AF: 0.408 AC: 7296 AN: 17888

South Asian (SAS) AF: 0.289 AC: 7118 AN: 24638

European-Finnish (FIN) AF: 0.307 AC: 2067 AN: 6742

Middle Eastern (MID) AF: 0.268 AC: 286 AN: 1066

European-Non Finnish (NFE) AF: 0.324 AC: 45416 AN: 140082

Other (OTH) AF: 0.312 AC: 4434 AN: 14210

GnomAD4 genome AF: 0.305 AC: 46376 AN: 151844 Hom.: 7150 Cov.: 32 AF XY: 0.305 AC XY: 22615 AN XY: 74190

African (AFR) AF: 0.258 AC: 10671 AN: 41420

American (AMR) AF: 0.288 AC: 4398 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 905 AN: 3470

East Asian (EAS) AF: 0.405 AC: 2088 AN: 5150

South Asian (SAS) AF: 0.321 AC: 1549 AN: 4826

European-Finnish (FIN) AF: 0.306 AC: 3210 AN: 10488

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.332 AC: 22539 AN: 67914

Other (OTH) AF: 0.297 AC: 627 AN: 2108

Alfa AF: 0.316 Hom.: 21050

Bravo AF: 0.298

Asia WGS AF: 0.306 AC: 1063 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.4
DANN	Benign	0.62
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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: rs1063053; hg19: chr8-90947537;