NM_002485.5:c.*1209A>C

Variant names:

• chr8-89934373-T-G
• rs1063054
• NM_002485.5:c.*1209A>C

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.*1209A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.323 in 232,660 control chromosomes in the GnomAD database, including 12,135 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7680 hom., cov: 32)
  • Exomes 𝑓: 0.33 (4455 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.108
• Publications: 32 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 8-89934373-T-G is Benign according to our data. Variant chr8-89934373-T-G is described in ClinVar as Benign. ClinVar VariationId is 363898.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.*1209A>C		3_prime_UTR	Exon 16 of 16	NP_002476.2
	NBN	NM_001024688.3		c.*1209A>C		3_prime_UTR	Exon 17 of 17	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.*1209A>C		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.*1209A>C		3_prime_UTR	Exon 16 of 16	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.*1075A>C		3_prime_UTR	Exon 15 of 15	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.*1209A>C		3_prime_UTR	Exon 17 of 17	ENSP00000513230.1	A0A8V8TM80

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48227 AN: 151928 Hom.: 7670 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.335

Gnomad AMR AF: 0.293

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.406

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.306

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.332 AC: 26803 AN: 80614 Hom.: 4455 Cov.: 0 AF XY: 0.332 AC XY: 12309 AN XY: 37044

African (AFR) AF: 0.295 AC: 1146 AN: 3880

American (AMR) AF: 0.301 AC: 748 AN: 2484

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 1387 AN: 5102

East Asian (EAS) AF: 0.409 AC: 4650 AN: 11362

South Asian (SAS) AF: 0.284 AC: 198 AN: 696

European-Finnish (FIN) AF: 0.393 AC: 22 AN: 56

Middle Eastern (MID) AF: 0.267 AC: 131 AN: 490

European-Non Finnish (NFE) AF: 0.329 AC: 16361 AN: 49794

Other (OTH) AF: 0.320 AC: 2160 AN: 6750

GnomAD4 genome AF: 0.317 AC: 48265 AN: 152046 Hom.: 7680 Cov.: 32 AF XY: 0.316 AC XY: 23521 AN XY: 74318

African (AFR) AF: 0.297 AC: 12319 AN: 41454

American (AMR) AF: 0.293 AC: 4478 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 905 AN: 3472

East Asian (EAS) AF: 0.406 AC: 2097 AN: 5170

South Asian (SAS) AF: 0.322 AC: 1550 AN: 4816

European-Finnish (FIN) AF: 0.306 AC: 3238 AN: 10572

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

European-Non Finnish (NFE) AF: 0.333 AC: 22646 AN: 67970

Other (OTH) AF: 0.306 AC: 646 AN: 2112

Alfa AF: 0.328 Hom.: 2869

Bravo AF: 0.312

Asia WGS AF: 0.310 AC: 1079 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.6
DANN	Benign	0.71
PhyloP100		-0.11
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: rs1063054; hg19: chr8-90946601;