rs13312981

Variant names:

• chr8-89934825-T-C
• rs13312981
• NM_002485.5:c.*757A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002485.5(NBN):​c.*757A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 232,942 control chromosomes in the GnomAD database, including 1,092 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.066 (989 hom., cov: 32)
  • Exomes 𝑓: 0.018 (103 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.941
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Myriad Women’s Health, G2P, Orphanet, ClinGen
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-89934825-T-C is Benign according to our data. Variant chr8-89934825-T-C is described in ClinVar as Benign. ClinVar VariationId is 363904.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.216 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.*757A>G		3_prime_UTR	Exon 16 of 16	NP_002476.2
	NBN	NM_001024688.3		c.*757A>G		3_prime_UTR	Exon 17 of 17	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.*757A>G		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.*757A>G		3_prime_UTR	Exon 16 of 16	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.*623A>G		3_prime_UTR	Exon 15 of 15	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.*757A>G		3_prime_UTR	Exon 17 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes AF: 0.0658 AC: 10007 AN: 152120 Hom.: 980 Cov.: 32

Gnomad AFR AF: 0.220

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0279

Gnomad ASJ AF: 0.0187

Gnomad EAS AF: 0.0115

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00266

Gnomad OTH AF: 0.0570

GnomAD4 exome AF: 0.0185 AC: 1489 AN: 80704 Hom.: 103 Cov.: 0 AF XY: 0.0171 AC XY: 634 AN XY: 37090

African (AFR) AF: 0.229 AC: 888 AN: 3880

American (AMR) AF: 0.0272 AC: 68 AN: 2496

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 100 AN: 5114

East Asian (EAS) AF: 0.00697 AC: 79 AN: 11338

South Asian (SAS) AF: 0.0214 AC: 15 AN: 700

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 56

Middle Eastern (MID) AF: 0.0102 AC: 5 AN: 492

European-Non Finnish (NFE) AF: 0.00267 AC: 133 AN: 49878

Other (OTH) AF: 0.0298 AC: 201 AN: 6750

GnomAD4 genome AF: 0.0661 AC: 10056 AN: 152238 Hom.: 989 Cov.: 32 AF XY: 0.0643 AC XY: 4788 AN XY: 74442

African (AFR) AF: 0.220 AC: 9134 AN: 41514

American (AMR) AF: 0.0278 AC: 426 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0187 AC: 65 AN: 3472

East Asian (EAS) AF: 0.0116 AC: 60 AN: 5188

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00266 AC: 181 AN: 68008

Other (OTH) AF: 0.0564 AC: 119 AN: 2110

Alfa AF: 0.0263 Hom.: 187

Bravo AF: 0.0758

Asia WGS AF: 0.0520 AC: 180 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Microcephaly, normal intelligence and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.8
DANN	Benign	0.70
PhyloP100		-0.94
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: rs13312981; hg19: chr8-90947053;