NM_002485.5:c.*1977T>C

Variant names:

• chr8-89933605-A-G
• rs14448
• NM_002485.5:c.*1977T>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.*1977T>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 0.165 in 232,030 control chromosomes in the GnomAD database, including 6,217 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.19 (5114 hom., cov: 32)
  • Exomes 𝑓: 0.12 (1103 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.44
• Publications: 21 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=-0.96).
• BP6: Variant 8-89933605-A-G is Benign according to our data. Variant chr8-89933605-A-G is described in ClinVar as Benign. ClinVar VariationId is 363892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.45 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.*1977T>C		3_prime_UTR	Exon 16 of 16	NP_002476.2
	NBN	NM_001024688.3		c.*1977T>C		3_prime_UTR	Exon 17 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.*1977T>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.*1977T>C		3_prime_UTR	Exon 16 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.*1843T>C		3_prime_UTR	Exon 15 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.*1977T>C		3_prime_UTR	Exon 17 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28888 AN: 152046 Hom.: 5086 Cov.: 32

Gnomad AFR AF: 0.455

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.189

Gnomad FIN AF: 0.0564

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0513

Gnomad OTH AF: 0.178

GnomAD4 exome AF: 0.116 AC: 9295 AN: 79866 Hom.: 1103 Cov.: 0 AF XY: 0.113 AC XY: 4155 AN XY: 36738

African (AFR) AF: 0.462 AC: 1765 AN: 3820

American (AMR) AF: 0.219 AC: 543 AN: 2476

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 361 AN: 5076

East Asian (EAS) AF: 0.282 AC: 3147 AN: 11140

South Asian (SAS) AF: 0.214 AC: 149 AN: 696

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

Middle Eastern (MID) AF: 0.0782 AC: 38 AN: 486

European-Non Finnish (NFE) AF: 0.0498 AC: 2463 AN: 49440

Other (OTH) AF: 0.124 AC: 828 AN: 6674

GnomAD4 genome AF: 0.190 AC: 28981 AN: 152164 Hom.: 5114 Cov.: 32 AF XY: 0.190 AC XY: 14156 AN XY: 74396

African (AFR) AF: 0.456 AC: 18882 AN: 41442

American (AMR) AF: 0.208 AC: 3176 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0648 AC: 225 AN: 3472

East Asian (EAS) AF: 0.239 AC: 1239 AN: 5180

South Asian (SAS) AF: 0.190 AC: 917 AN: 4832

European-Finnish (FIN) AF: 0.0564 AC: 598 AN: 10606

Middle Eastern (MID) AF: 0.0680 AC: 20 AN: 294

European-Non Finnish (NFE) AF: 0.0513 AC: 3490 AN: 68026

Other (OTH) AF: 0.185 AC: 392 AN: 2116

Alfa AF: 0.102 Hom.: 2414

Bravo AF: 0.215

Asia WGS AF: 0.295 AC: 1026 AN: 3476

ClinVar

ClinVar submissions as Germline

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	-0.96
CADD	Benign	0.53
DANN	Benign	0.52
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs14448; hg19: chr8-90945833; COSMIC: COSV55375146; COSMIC: COSV55375146;