rs61754795

Positions:

• chr8-89980833-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000265433.8(NBN):​c.381T>C​(p.Ala127=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00448 in 1,612,660 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0027 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (29 hom.)
• Consequence: NBN ENST00000265433.8 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19 O:1
• Conservation: PhyloP100: 1.43

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 8-89980833-A-G is Benign according to our data. Variant chr8-89980833-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 132744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-89980833-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.43 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00274 (418/152320) while in subpopulation SAS AF= 0.00559 (27/4832). AF 95% confidence interval is 0.00394. There are 1 homozygotes in gnomad4. There are 202 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 29 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.381T>C	p.Ala127=	synonymous_variant	4/16	ENST00000265433.8	NP_002476.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.381T>C	p.Ala127=	synonymous_variant	4/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 419 AN: 152202 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00294

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00558

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00413

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00317 AC: 797 AN: 251186 Hom.: 5 AF XY: 0.00368 AC XY: 500 AN XY: 135764

Gnomad AFR exome AF: 0.00123

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00774

Gnomad FIN exome AF: 0.000884

Gnomad NFE exome AF: 0.00395

Gnomad OTH exome AF: 0.00261

GnomAD4 exome AF: 0.00466 AC: 6811 AN: 1460340 Hom.: 29 Cov.: 31 AF XY: 0.00474 AC XY: 3443 AN XY: 726602

Gnomad4 AFR exome AF: 0.000658

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00649

Gnomad4 FIN exome AF: 0.000958

Gnomad4 NFE exome AF: 0.00524

Gnomad4 OTH exome AF: 0.00416

GnomAD4 genome AF: 0.00274 AC: 418 AN: 152320 Hom.: 1 Cov.: 32 AF XY: 0.00271 AC XY: 202 AN XY: 74480

Gnomad4 AFR AF: 0.00130

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00559

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00413

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00348 Hom.: 0

Bravo AF: 0.00266

Asia WGS AF: 0.00116 AC: 4 AN: 3474

EpiCase AF: 0.00354

EpiControl AF: 0.00385

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5 Other:1

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The NBN p.Ala127Ala variant was identified in 1 of 194 proband chromosomes (frequency: 0.005) from French Canadian individuals or families non BRCA1/2 breast cancer and was not identified in 144 control chromosomes from healthy individuals (Desjardins 2009). The variant was also identified in dbSNP (ID: rs61754795) “With other allele”, ClinVar (classified benign by GeneDx, EGL Genetic Diagnostics (Eurofins Clinical Diagnsotics), Color Genomics Inc, Invitae; likely benign by Ambry Genetics and Lab for Molecular Medicine (Partners HealthCare Personalized Medicine); and classification not provided by Harris Lab (U of Minnesota)), Clinvitae (4x), and was not identified in Cosmic, LOVD 3.0, Zhejiang Colon Cancer Database. The variant was identified in control databases in 858 (4 homozygous) of 276910 chromosomes at a frequency of 0.003 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 26 of 24026 chromosomes (frequency: 0.001), Other in 16 of 6456 chromosomes (frequency: 0.002), Latino in 54 of 34414 chromosomes (frequency: 0.002), European Non-Finnish in 499 of 126588 chromosomes (frequency: 0.004), European Finnish in 20 of 25630 chromosomes (frequency: 0.0008), Ashkenazi Jewish in 4 of 10150 chromosomes (frequency: 0.0004), and South Asian in 239 (4 homozygotes) of 30782 chromosomes (frequency: 0.008). The p.Ala127= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 24, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Nov 15, 2022	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	NBN: BP4, BS2 -
not provided, no classification provided	literature only	Harris Lab, University of Minnesota	-	- -

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 27, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 24, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Multiple assertions in clinvar as benign for hereditary cancer predisposing syndrome and microcephaly with normal intelligence and immunodeficiency -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 27, 2021	- -

Hereditary cancer-predisposing syndrome Benign:4

Likely benign, no assertion criteria provided	clinical testing	True Health Diagnostics	Sep 21, 2017	- -
Benign, criteria provided, single submitter	curation	Sema4, Sema4	Mar 23, 2020	- -
Likely benign, no assertion criteria provided	clinical testing	Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	Sep 27, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 01, 2014	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Microcephaly, normal intelligence and immunodeficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 23, 2021

- -

Acute lymphoid leukemia Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.77

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: rs61754795; hg19: chr8-90993061; COSMIC: COSV104545489; COSMIC: COSV104545489;