rs61754795

Variant names:

• chr8-89980833-A-G
• rs61754795
• NM_002485.5:c.381T>C
• NBN p.Ala127Ala

Your query was ambiguous. Multiple possible variants found:

• chr8-89980833-A-G
• chr8-89980833-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002485.5(NBN):​c.381T>C​(p.Ala127Ala) 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 NM_002485.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:21 O:1
• Conservation: PhyloP100: 1.43
• Publications: 7 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: Labcorp Genetics (formerly Invitae), G2P, Myriad Women's Health, ClinGen, Orphanet
• 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 132744.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 29 AR,AD gene

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.381T>C	p.Ala127Ala	synonymous	Exon 4 of 16	NP_002476.2
	NBN	NM_001024688.3		c.135T>C	p.Ala45Ala	synonymous	Exon 5 of 17	NP_001019859.1	A0A0C4DG07
	NBN	NM_001440379.1		c.135T>C	p.Ala45Ala	synonymous	Exon 4 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.381T>C	p.Ala127Ala	synonymous	Exon 4 of 16	ENSP00000265433.4	O60934
	NBN	ENST00000697309.1		c.381T>C	p.Ala127Ala	synonymous	Exon 4 of 15	ENSP00000513244.1	A0A8V8TKY5
	NBN	ENST00000697293.1		c.381T>C	p.Ala127Ala	synonymous	Exon 4 of 17	ENSP00000513230.1	A0A8V8TM80

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

GnomAD2 exomes AF: 0.00317 AC: 797 AN: 251186 AF XY: 0.00368

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 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

African (AFR) AF: 0.000658 AC: 22 AN: 33436

American (AMR) AF: 0.00201 AC: 90 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00649 AC: 560 AN: 86232

European-Finnish (FIN) AF: 0.000958 AC: 51 AN: 53236

Middle Eastern (MID) AF: 0.00226 AC: 13 AN: 5758

European-Non Finnish (NFE) AF: 0.00524 AC: 5817 AN: 1110866

Other (OTH) AF: 0.00416 AC: 251 AN: 60360

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

African (AFR) AF: 0.00130 AC: 54 AN: 41570

American (AMR) AF: 0.00294 AC: 45 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00559 AC: 27 AN: 4832

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00413 AC: 281 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00378 Hom.: 0

Bravo AF: 0.00266

Asia WGS AF: 0.00116 AC: 4 AN: 3474

EpiCase AF: 0.00354

EpiControl AF: 0.00385

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	not provided (6)
-	-	4	Hereditary cancer-predisposing syndrome (4)
-	-	4	Microcephaly, normal intelligence and immunodeficiency (4)
-	-	1	Acute lymphoid leukemia (1)
-	-	1	Aplastic anemia;C0023449:Acute lymphoid leukemia;C0398791:Microcephaly, normal intelligence and immunodeficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	12
DANN	Benign	0.77
PhyloP100		1.4
Mutation Taster		=100/0	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

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