ENST00000846143.1:n.585_588delTTAC

Variant names:

• chr8-89984909-ATACT-A
• rs36226237
• ENST00000846143.1:n.585_588delTTAC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The ENST00000846143.1(ENSG00000309953):​n.585_588delTTAC variant causes a non coding transcript exon 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: ENSG00000309953 ENST00000846143.1 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.178
• Publications: 4 publications found

Genes affected

ENSG00000309953 (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]

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 -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 VariationId 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 rank	MANE	Protein	UniProt
NBN	NM_002485.5	c.-352_-349delAGTA		upstream_gene_variant		ENST00000265433.8	NP_002476.2
NBN	NM_001024688.3	c.-648_-645delAGTA		upstream_gene_variant			NP_001019859.1
NBN	XM_011517046.2	c.-352_-349delAGTA		upstream_gene_variant			XP_011515348.1
NBN	XM_047421796.1	c.-352_-349delAGTA		upstream_gene_variant			XP_047277752.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.-352_-349delAGTA		upstream_gene_variant		1	NM_002485.5	ENSP00000265433.4

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

African (AFR) AF: 0.00972 AC: 61 AN: 6278

American (AMR) AF: 0.0150 AC: 105 AN: 7000

Ashkenazi Jewish (ASJ) AF: 0.0435 AC: 347 AN: 7978

East Asian (EAS) AF: 0.00 AC: 0 AN: 16936

South Asian (SAS) AF: 0.0118 AC: 155 AN: 13132

European-Finnish (FIN) AF: 0.0336 AC: 399 AN: 11860

Middle Eastern (MID) AF: 0.0209 AC: 22 AN: 1052

European-Non Finnish (NFE) AF: 0.0464 AC: 5924 AN: 127690

Other (OTH) AF: 0.0337 AC: 469 AN: 13902

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

African (AFR) AF: 0.00892 AC: 371 AN: 41588

American (AMR) AF: 0.0196 AC: 300 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 169 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5192

South Asian (SAS) AF: 0.0130 AC: 63 AN: 4830

European-Finnish (FIN) AF: 0.0369 AC: 392 AN: 10626

Middle Eastern (MID) AF: 0.0272 AC: 8 AN: 294

European-Non Finnish (NFE) AF: 0.0516 AC: 3511 AN: 68022

Other (OTH) AF: 0.0204 AC: 43 AN: 2112

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

Feb 07, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19523210) -

Nov 28, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Microcephaly, normal intelligence and immunodeficiency Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.18

Splicing

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

Other links and lift over

dbSNP: rs36226237; hg19: chr8-90997137;