rs1554569682

Positions:

• chr8-89984559-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PS1_Moderate PM2

The NM_002485.5(NBN):​c.3G>A​(p.Met1?) variant causes a start lost change. The variant allele was found at a frequency of 0.000000685 in 1,460,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NBN NM_002485.5 start_lost
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.64

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_002485.5 (NBN) was described as [Likely_pathogenic] in Lovd
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBN	NM_002485.5	c.3G>A	p.Met1?	start_lost	1/16	ENST00000265433.8	NP_002476.2
NBN	XM_011517046.2	c.3G>A	p.Met1?	start_lost	1/11		XP_011515348.1
NBN	XM_047421796.1	c.3G>A	p.Met1?	start_lost	1/10		XP_047277752.1
NBN	NM_001024688.3	c.-294G>A		5_prime_UTR_variant	1/17		NP_001019859.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBN	ENST00000265433.8	c.3G>A	p.Met1?	start_lost	1/16	1	NM_002485.5	ENSP00000265433	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460816 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726782

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly, normal intelligence and immunodeficiency Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2020	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant at the initiator codon is expected to affect translation initiation. Rescue of translation at the next in-frame methionine at codon 83 is expected to disrupt the forkhead-associated (FHA) domain (PMID: 9590180, 26315354), which facilitates DNA repair responses (PMID: 11062235, 19804755, 12433983). However, functional study has not been tested for this variant. A different change affecting the initiator codon (c.1A>G) has been observed as homozygous in an individual affected with colorectal cancer (PMID: 28975465). Biallelic pathogenic NBN variants are associated with autosomal recessive Nijimegen breakage syndrome (NBS). Therefore, the clinical significance of this observation is uncertain. This variant has not been reported in the literature in individuals with NBN-related disease. ClinVar contains an entry for this variant (Variation ID: 461561). This variant is not present in population databases (ExAC no frequency). This sequence change affects the initiator methionine of the NBN mRNA. The next in-frame methionine is located at codon 83. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Nov 07, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Pathogenic	0.22
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.089	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Uncertain	-0.050	T
MutationTaster	Benign	1.0	D
PROVEAN	Uncertain	-2.6	D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		0.98	D;.
Vest4		0.92
MutPred		0.95		Loss of disorder (P = 0.0695);Loss of disorder (P = 0.0695);
MVP		0.80
ClinPred		1.0	D
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.92
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1554569682; hg19: chr8-90996787;