8-89953700-TAAAA-TAAAAA

Position:

• chr8-89953700-TAAAA-TAAAAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_002485.5(NBN):​c.1398-10dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000479 in 1,580,906 control chromosomes in the GnomAD database, including 3 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (3 hom.)
• Consequence: NBN NM_002485.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.25

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 8-89953700-T-TA is Benign according to our data. Variant chr8-89953700-T-TA is described in ClinVar as [Likely_benign]. Clinvar id is 132766.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000479 (685/1429888) while in subpopulation MID AF= 0.0092 (49/5326). AF 95% confidence interval is 0.00715. There are 3 homozygotes in gnomad4_exome. There are 373 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.1398-10dupT		intron_variant		ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.1398-10dupT		intron_variant		1	NM_002485.5	ENSP00000265433.4

Frequencies

GnomAD3 genomes AF: 0.000477 AC: 72 AN: 150904 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000341

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000331

Gnomad ASJ AF: 0.00377

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00167

Gnomad FIN AF: 0.0000967

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000325

Gnomad OTH AF: 0.00193

GnomAD4 exome AF: 0.000479 AC: 685 AN: 1429888 Hom.: 3 Cov.: 30 AF XY: 0.000524 AC XY: 373 AN XY: 711362

Gnomad4 AFR exome AF: 0.000399

Gnomad4 AMR exome AF: 0.000843

Gnomad4 ASJ exome AF: 0.00266

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.00209

Gnomad4 FIN exome AF: 0.000182

Gnomad4 NFE exome AF: 0.000260

Gnomad4 OTH exome AF: 0.000762

GnomAD4 genome AF: 0.000477 AC: 72 AN: 151018 Hom.: 0 Cov.: 32 AF XY: 0.000502 AC XY: 37 AN XY: 73764

Gnomad4 AFR AF: 0.000340

Gnomad4 AMR AF: 0.000330

Gnomad4 ASJ AF: 0.00377

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00167

Gnomad4 FIN AF: 0.0000967

Gnomad4 NFE AF: 0.000325

Gnomad4 OTH AF: 0.00191

Bravo AF: 0.000378

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 26, 2024	Variant summary: NBN c.1398-10dupT alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00048 in 1580906 control chromosomes, predominantly at a frequency of 0.0021 within the South Asian subpopulation in the gnomAD database, including 3 homozygotes. This frequency is not significantly higher than estimated for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome (0.00048 vs 0.0025), allowing no conclusion about variant significance. To our knowledge, no occurrence of c.1398-10dupT in individuals affected with Nijmegen Breakage Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 132766). Based on the evidence outlined above, the variant was classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 20, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 07, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Apr 15, 2021	- -

Hereditary cancer-predisposing syndrome Benign:2

Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Jul 09, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Mar 14, 2024	- -

Microcephaly, normal intelligence and immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs587780555; hg19: chr8-90965928;