rs780333168

Variant names:

• chr8-89943306-G-A
• rs780333168
• NM_002485.5:c.2131C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002485.5(NBN):​c.2131C>T​(p.His711Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H711L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NBN NM_002485.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 2.35
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	NM_002485.5	MANE Select	c.2131C>T	p.His711Tyr	missense	Exon 14 of 16	NP_002476.2
	NBN	NM_001024688.3		c.1885C>T	p.His629Tyr	missense	Exon 15 of 17	NP_001019859.1
	NBN	NM_001440379.1		c.1885C>T	p.His629Tyr	missense	Exon 14 of 16	NP_001427308.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBN	ENST00000265433.8	TSL:1 MANE Select	c.2131C>T	p.His711Tyr	missense	Exon 14 of 16	ENSP00000265433.4
	NBN	ENST00000697309.1		c.2131C>T	p.His711Tyr	missense	Exon 14 of 15	ENSP00000513244.1
	NBN	ENST00000697293.1		c.2131C>T	p.His711Tyr	missense	Exon 14 of 17	ENSP00000513230.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000329 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Microcephaly, normal intelligence and immunodeficiency (3)
-	1	-	Aplastic anemia (1)
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Benign	0.0098
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.034	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.3
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.17
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.15	B
Vest4		0.19
MutPred		0.76		Loss of helix (P = 0.0068)
MVP		0.76
MPC		0.16
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.24
gMVP		0.54
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs780333168; hg19: chr8-90955534;