8-89996055-A-T

Variant names:

• chr8-89996055-A-T
• rs926092
• ENST00000396252.6:n.-230+7057T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000396252.6(NBN):​n.-230+7057T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.309 in 151,892 control chromosomes in the GnomAD database, including 7,498 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.31 (7498 hom., cov: 31)
• Consequence: NBN ENST00000396252.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0890
• Publications: 5 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

ENSG00000298563 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.436 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000396252.6	n.-230+7057T>A		intron_variant	Intron 1 of 18	5		ENSP00000379551.2
ENSG00000298563	ENST00000756462.1	n.219-4750T>A		intron_variant	Intron 1 of 1

Frequencies

GnomAD3 genomes AF: 0.309 AC: 46914 AN: 151776 Hom.: 7490 Cov.: 31

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.268

Gnomad AMR AF: 0.341

Gnomad ASJ AF: 0.308

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.437

Gnomad FIN AF: 0.353

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.325

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.309 AC: 46941 AN: 151892 Hom.: 7498 Cov.: 31 AF XY: 0.315 AC XY: 23347 AN XY: 74220

African (AFR) AF: 0.231 AC: 9580 AN: 41458

American (AMR) AF: 0.342 AC: 5210 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.308 AC: 1069 AN: 3470

East Asian (EAS) AF: 0.451 AC: 2318 AN: 5136

South Asian (SAS) AF: 0.438 AC: 2112 AN: 4818

European-Finnish (FIN) AF: 0.353 AC: 3702 AN: 10498

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

European-Non Finnish (NFE) AF: 0.323 AC: 21931 AN: 67956

Other (OTH) AF: 0.329 AC: 693 AN: 2106

Alfa AF: 0.189 Hom.: 414

Bravo AF: 0.301

Asia WGS AF: 0.421 AC: 1465 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.3
DANN	Benign	0.77
PhyloP100		-0.089

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs926092; hg19: chr8-91008283;