rs1060504925

Variant names:

• chr8-89947898-GAAATA-G
• rs1060504925
• NM_002485.5:c.1846-11_1846-7delTATTT

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP6

The NM_002485.5(NBN):​c.1846-11_1846-7delTATTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000656 in 1,370,998 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000066 (0 hom.)
• Consequence: NBN NM_002485.5 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 3.31
• Publications: 0 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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP6: Variant 8-89947898-GAAATA-G is Benign according to our data. Variant chr8-89947898-GAAATA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 416880.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002485.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.1846-11_1846-7delTATTT		splice_region intron	N/A	NP_002476.2
	NBN	NM_001024688.3		c.1600-11_1600-7delTATTT		splice_region intron	N/A	NP_001019859.1
	NBN	NM_001440379.1		c.1600-11_1600-7delTATTT		splice_region intron	N/A	NP_001427308.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.1846-11_1846-7delTATTT		splice_region intron	N/A	ENSP00000265433.4
	NBN	ENST00000697306.1		n.*858_*862delTATTT		non_coding_transcript_exon	Exon 8 of 11	ENSP00000513241.1
	NBN	ENST00000697306.1		n.*858_*862delTATTT		3_prime_UTR	Exon 8 of 11	ENSP00000513241.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000656 AC: 9 AN: 1370998 Hom.: 0 AF XY: 0.00000586 AC XY: 4 AN XY: 682714

African (AFR) AF: 0.00 AC: 0 AN: 31012

American (AMR) AF: 0.00 AC: 0 AN: 42046

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25038

East Asian (EAS) AF: 0.00 AC: 0 AN: 37762

South Asian (SAS) AF: 0.0000247 AC: 2 AN: 80868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5512

European-Non Finnish (NFE) AF: 0.00000672 AC: 7 AN: 1041090

Other (OTH) AF: 0.00 AC: 0 AN: 56922

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)
-	-	1	Microcephaly, normal intelligence and immunodeficiency (1)
-	-	1	NBN-related disorder (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.3
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1060504925; hg19: chr8-90960126;