rs36226237

Positions:

• chr8-89984909-ATACT-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000396252.6(NBN):​n.-173+4_-173+7delAGTA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0346 in 358,176 control chromosomes in the GnomAD database, including 327 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (125 hom., cov: 32)
  • Exomes 𝑓: 0.036 (202 hom.)
• Consequence: NBN ENST00000396252.6 splice_region, intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.178

Genes affected

(HGNC:):

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 -16 ACMG points.

• BP6: Variant 8-89984909-ATACT-A is Benign according to our data. Variant chr8-89984909-ATACT-A is described in ClinVar as [Benign]. Clinvar id is 1164691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0502 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.89984910_89984913delTACT		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000396252.6	n.-173+4_-173+7delAGTA		splice_region_variant, intron_variant		5		ENSP00000379551.2

Frequencies

GnomAD3 genomes AF: 0.0323 AC: 4913 AN: 152230 Hom.: 125 Cov.: 32

Gnomad AFR AF: 0.00897

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0196

Gnomad ASJ AF: 0.0487

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0132

Gnomad FIN AF: 0.0369

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0516

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.0364 AC: 7482 AN: 205828 Hom.: 202 AF XY: 0.0363 AC XY: 3776 AN XY: 104062

Gnomad4 AFR exome AF: 0.00972

Gnomad4 AMR exome AF: 0.0150

Gnomad4 ASJ exome AF: 0.0435

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0118

Gnomad4 FIN exome AF: 0.0336

Gnomad4 NFE exome AF: 0.0464

Gnomad4 OTH exome AF: 0.0337

GnomAD4 genome AF: 0.0322 AC: 4912 AN: 152348 Hom.: 125 Cov.: 32 AF XY: 0.0299 AC XY: 2231 AN XY: 74502

Gnomad4 AFR AF: 0.00892

Gnomad4 AMR AF: 0.0196

Gnomad4 ASJ AF: 0.0487

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0130

Gnomad4 FIN AF: 0.0369

Gnomad4 NFE AF: 0.0516

Gnomad4 OTH AF: 0.0204

Alfa AF: 0.0447 Hom.: 23

Bravo AF: 0.0306

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2019	This variant is associated with the following publications: (PMID: 19523210) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

Microcephaly, normal intelligence and immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs36226237; hg19: chr8-90997137;