rs12721593

chr8-89981417-G-Achr8-89981417-G-Cchr8-89981417-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002485.5(NBN):c.278C>T(p.Ser93Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000366 in 1,613,852 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S93A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00039 (5 hom.)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:6
• Conservation: PhyloP100: 7.17

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013203561).
• BP6: Variant 8-89981417-G-A is Benign according to our data. Variant chr8-89981417-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 142227.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=5, Likely_benign=5, Benign=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000158 (24/152122) while in subpopulation SAS AF= 0.00393 (19/4830). AF 95% confidence interval is 0.00258. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBN	NM_002485.5	c.278C>T	p.Ser93Leu	missense_variant	3/16	ENST00000265433.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBN	ENST00000265433.8	c.278C>T	p.Ser93Leu	missense_variant	3/16	1	NM_002485.5	P1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000581 AC: 146 AN: 251376 Hom.: 2 AF XY: 0.000795 AC XY: 108 AN XY: 135880

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00428

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000967

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000388 AC: 567 AN: 1461730 Hom.: 5 Cov.: 31 AF XY: 0.000539 AC XY: 392 AN XY: 727164

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00453

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000138

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74350

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000870 Hom.: 0

Bravo AF: 0.0000529

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.000725 AC: 88

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:3 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	Apr 29, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	May 18, 2021	- -

Hereditary cancer-predisposing syndrome Uncertain:1 Benign:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneKor MSA	Aug 01, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 01, 2019	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. -
Likely benign, criteria provided, single submitter	curation	Sema4, Sema4	Feb 01, 2021	- -

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 13, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 17, 2021	Variant summary: NBN c.278C>T (p.Ser93Leu) results in a non-conservative amino acid change located in the Forkhead-associated (FHA) domain (IPR000253) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00058 in 251486 control chromosomes, predominantly at a frequency of 0.0043 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in NBN causing Nijmegen Breakage Syndrome phenotype (0.0025), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.278C>T has been reported in the literature in individuals affected with cancer (example: Varon_2001, Taylor_2003, Ramus_2015, Yurgelun_2017, Tsaousis_2019, Dorling_2021). These data do not allow any conclusion about variant significance with Nijmegen Breakage Syndrome or increase risk in cancer. Co-occurrence with other pathogenic variants has been reported (BRCA c.7251_7252delCA, p.H2417fs*3), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine ClinVar submitters have assessed the variant since 2014: five as uncertain significance, three as likely benign, and one as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2020	This variant is associated with the following publications: (PMID: 25980754, 11325820, 14559852, 28135145, 25176580, 19452044, 15279809, 26315354, 31278556, 31159747) -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 12, 2022	- -

Malignant tumor of breast Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

The NBN p.Ser93Leu variant was identified in 1 of 94 proband chromosomes (frequency: 0.01) from German individuals or families with acute lymphocytic leukemia (ALL) and was not identified in 110 control chromosomes from healthy individuals (Varon 2001). The variant was also identified in dbSNP (ID: rs12721593 “With Uncertain significance allele”), ClinVar (1x as likely benign by Invitae and 3x as uncertain significance by Ambry Genetics, GeneDx, and Genetic Services Laboratory at University of Chicago), LOVD 3.0 (1x), and the Zhejiang University Database (3x). The variant was also identified in control databases in 148 of 246182 chromosomes (2 homozygous) at a frequency of 0.0006 (Genome Aggregation Consortium Feb 27, 2017), being identified in the following populations: African in 1 of 15292 chromosomes (frequency: 0.00007), Latino in 3 of 33576 chromosomes (frequency 0.00009), European Non-Finnish in 11 of 111668 chromosomes (frequency: 0.0001) and South Asian in 133 of 30778 chromosomes (2 homozygous, frequency: 0.004). The variant was not identified in Cosmic. The p.Ser93Leu variant occurs in the known FHA (forkhead associated) domain of nibrin that is probably involved in protein-protein interactions (Di Masi 2008, Digweed 2004). The p.Ser93 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact of the Leu variant to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and 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. This variant is classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;.;.;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
M_CAP	Benign	0.081	D
MetaRNN	Benign	0.013	T;T;T;T;T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Uncertain	2.0	M;.;.;.;.
MutationTaster	Benign	0.88	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0040	D;D;D;D;T
Sift4G	Uncertain	0.041	D;D;D;.;D
Polyphen		0.94	P;.;.;.;.
Vest4		0.23
MVP		0.95
MPC		0.11
ClinPred		0.10	T
GERP RS		5.7
Varity_R		0.30
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs12721593; hg19: chr8-90993645; COSMIC: COSV99619962; COSMIC: COSV99619962;