chr8-89933828-A-G

Variant names:

• chr8-89933828-A-G
• rs9995
• NM_002485.5:c.*1754T>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.*1754T>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 0.322 in 232,162 control chromosomes in the GnomAD database, including 12,096 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (7671 hom., cov: 31)
  • Exomes 𝑓: 0.33 (4425 hom.)
• Consequence: NBN NM_002485.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.468
• 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=-0.95).
• BP6: Variant 8-89933828-A-G is Benign according to our data. Variant chr8-89933828-A-G is described in ClinVar as [Benign]. Clinvar id is 363896.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.*1754T>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.*1754T>C		3_prime_UTR_variant	Exon 16 of 16	1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.317 AC: 48195 AN: 151926 Hom.: 7661 Cov.: 31

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.292

Gnomad ASJ AF: 0.261

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.318

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.333

Gnomad OTH AF: 0.308

GnomAD4 exome AF: 0.332 AC: 26633 AN: 80122 Hom.: 4425 Cov.: 0 AF XY: 0.332 AC XY: 12251 AN XY: 36874

African (AFR) AF: 0.296 AC: 1143 AN: 3868

American (AMR) AF: 0.301 AC: 750 AN: 2488

Ashkenazi Jewish (ASJ) AF: 0.272 AC: 1385 AN: 5090

East Asian (EAS) AF: 0.410 AC: 4579 AN: 11172

South Asian (SAS) AF: 0.277 AC: 192 AN: 692

European-Finnish (FIN) AF: 0.397 AC: 23 AN: 58

Middle Eastern (MID) AF: 0.263 AC: 128 AN: 486

European-Non Finnish (NFE) AF: 0.329 AC: 16284 AN: 49552

Other (OTH) AF: 0.320 AC: 2149 AN: 6716

GnomAD4 genome AF: 0.317 AC: 48232 AN: 152040 Hom.: 7671 Cov.: 31 AF XY: 0.316 AC XY: 23503 AN XY: 74334

African (AFR) AF: 0.297 AC: 12312 AN: 41462

American (AMR) AF: 0.292 AC: 4467 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.261 AC: 904 AN: 3464

East Asian (EAS) AF: 0.406 AC: 2101 AN: 5178

South Asian (SAS) AF: 0.320 AC: 1541 AN: 4812

European-Finnish (FIN) AF: 0.305 AC: 3226 AN: 10568

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

European-Non Finnish (NFE) AF: 0.333 AC: 22647 AN: 67962

Other (OTH) AF: 0.306 AC: 644 AN: 2108

Alfa AF: 0.319 Hom.: 10082

Bravo AF: 0.312

Asia WGS AF: 0.309 AC: 1075 AN: 3478

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	-0.95
CADD	Benign	1.0
DANN	Benign	0.40
PhyloP100		-0.47
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: rs9995; hg19: chr8-90946056;