8-89953700-TAAAA-TAAAAA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_002485.5(NBN):c.1398-10_1398-9insT variant causes a splice polypyrimidine tract, 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 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• 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]

ACMG classification

Verdict is Benign. Variant got -12 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.1398-10_1398-9insT		splice_polypyrimidine_tract_variant, intron_variant		ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.1398-10_1398-9insT		splice_polypyrimidine_tract_variant, intron_variant		1	NM_002485.5	P1

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 20, 2021	- -

not provided Benign:2

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

Hereditary cancer-predisposing syndrome Benign:2

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

Microcephaly, normal intelligence and immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

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;