rs13312986

Variant names:

• chr8-89933890-T-C
• rs13312986
• NM_002485.5:c.*1692A>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.*1692A>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 0.0378 in 232,162 control chromosomes in the GnomAD database, including 456 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.033 (226 hom., cov: 32)
  • Exomes 𝑓: 0.046 (230 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.29
• Publications: 9 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 8-89933890-T-C is Benign according to our data. Variant chr8-89933890-T-C is described in ClinVar as Benign. ClinVar VariationId is 363897.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.163 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.*1692A>G		3_prime_UTR	Exon 16 of 16	NP_002476.2
	NBN	NM_001024688.3		c.*1692A>G		3_prime_UTR	Exon 17 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.*1692A>G		3_prime_UTR	Exon 16 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.*1692A>G		3_prime_UTR	Exon 16 of 16	ENSP00000265433.4
	NBN	ENST00000396252.6	TSL:5	n.*3830A>G		non_coding_transcript_exon	Exon 19 of 19	ENSP00000379551.2
	NBN	ENST00000474821.2	TSL:2	n.5377A>G		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.0332 AC: 5054 AN: 152082 Hom.: 224 Cov.: 32

Gnomad AFR AF: 0.00517

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.111

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.172

Gnomad SAS AF: 0.0716

Gnomad FIN AF: 0.0476

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0187

Gnomad OTH AF: 0.0373

GnomAD4 exome AF: 0.0465 AC: 3718 AN: 79960 Hom.: 230 Cov.: 0 AF XY: 0.0461 AC XY: 1696 AN XY: 36752

African (AFR) AF: 0.00545 AC: 21 AN: 3852

American (AMR) AF: 0.123 AC: 306 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.00730 AC: 37 AN: 5070

East Asian (EAS) AF: 0.195 AC: 2172 AN: 11152

South Asian (SAS) AF: 0.0939 AC: 65 AN: 692

European-Finnish (FIN) AF: 0.0172 AC: 1 AN: 58

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 486

European-Non Finnish (NFE) AF: 0.0179 AC: 885 AN: 49472

Other (OTH) AF: 0.0345 AC: 231 AN: 6694

GnomAD4 genome AF: 0.0333 AC: 5062 AN: 152202 Hom.: 226 Cov.: 32 AF XY: 0.0369 AC XY: 2749 AN XY: 74406

African (AFR) AF: 0.00515 AC: 214 AN: 41536

American (AMR) AF: 0.111 AC: 1698 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00605 AC: 21 AN: 3470

East Asian (EAS) AF: 0.172 AC: 892 AN: 5174

South Asian (SAS) AF: 0.0717 AC: 346 AN: 4826

European-Finnish (FIN) AF: 0.0476 AC: 504 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0187 AC: 1270 AN: 68010

Other (OTH) AF: 0.0383 AC: 81 AN: 2114

Alfa AF: 0.0250 Hom.: 358

Bravo AF: 0.0387

Asia WGS AF: 0.126 AC: 435 AN: 3472

ClinVar

ClinVar submissions as Germline

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	-0.93
CADD	Benign	2.5
DANN	Benign	0.70
PhyloP100		-1.3
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: rs13312986; hg19: chr8-90946118;