rs14448

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.*1977T>C		3_prime_UTR_variant	Exon 16 of 16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.*1977T>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_002485.5	ENSP00000265433.4

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

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

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;