rs2277439

Variant names:

• chr13-42581307-G-A
• rs2277439
• NM_003701.4:c.387+14G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003701.4(TNFSF11):​c.387+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 1,613,398 control chromosomes in the GnomAD database, including 544,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49680 hom., cov: 31)
  • Exomes 𝑓: 0.82 (494565 hom.)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.49
• Publications: 25 publications found

Genes affected

TNFSF11 (HGNC:11926): (TNF superfamily member 11) This gene encodes a member of the tumor necrosis factor (TNF) cytokine family which is a ligand for osteoprotegerin and functions as a key factor for osteoclast differentiation and activation. This protein was shown to be a dentritic cell survival factor and is involved in the regulation of T cell-dependent immune response. T cell activation was reported to induce expression of this gene and lead to an increase of osteoclastogenesis and bone loss. This protein was shown to activate antiapoptotic kinase AKT/PKB through a signaling complex involving SRC kinase and tumor necrosis factor receptor-associated factor (TRAF) 6, which indicated this protein may have a role in the regulation of cell apoptosis. Targeted disruption of the related gene in mice led to severe osteopetrosis and a lack of osteoclasts. The deficient mice exhibited defects in early differentiation of T and B lymphocytes, and failed to form lobulo-alveolar mammary structures during pregnancy. Two alternatively spliced transcript variants have been found. [provided by RefSeq, Jul 2008]

TNFSF11 Gene-Disease associations (from GenCC):

• autosomal recessive osteopetrosis 2

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• autosomal recessive osteopetrosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 13-42581307-G-A is Benign according to our data. Variant chr13-42581307-G-A is described in ClinVar as Benign. ClinVar VariationId is 195202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF11	NM_003701.4	c.387+14G>A		intron_variant	Intron 2 of 4	ENST00000398795.7	NP_003692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF11	ENST00000398795.7	c.387+14G>A		intron_variant	Intron 2 of 4	1	NM_003701.4	ENSP00000381775.3
TNFSF11	ENST00000358545.6	c.168+14G>A		intron_variant	Intron 4 of 6	1		ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122624 AN: 152028 Hom.: 49646 Cov.: 31

Gnomad AFR AF: 0.803

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.883

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.809

GnomAD2 exomes AF: 0.801 AC: 200955 AN: 250922 AF XY: 0.812

Gnomad AFR exome AF: 0.806

Gnomad AMR exome AF: 0.623

Gnomad ASJ exome AF: 0.819

Gnomad EAS exome AF: 0.695

Gnomad FIN exome AF: 0.871

Gnomad NFE exome AF: 0.833

Gnomad OTH exome AF: 0.813

GnomAD4 exome AF: 0.821 AC: 1200085 AN: 1461252 Hom.: 494565 Cov.: 46 AF XY: 0.824 AC XY: 599325 AN XY: 726956

African (AFR) AF: 0.807 AC: 26992 AN: 33460

American (AMR) AF: 0.628 AC: 28068 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.821 AC: 21439 AN: 26128

East Asian (EAS) AF: 0.673 AC: 26716 AN: 39670

South Asian (SAS) AF: 0.884 AC: 76238 AN: 86218

European-Finnish (FIN) AF: 0.869 AC: 46420 AN: 53398

Middle Eastern (MID) AF: 0.857 AC: 4942 AN: 5768

European-Non Finnish (NFE) AF: 0.828 AC: 919819 AN: 1111536

Other (OTH) AF: 0.819 AC: 49451 AN: 60378

GnomAD4 genome AF: 0.807 AC: 122706 AN: 152146 Hom.: 49680 Cov.: 31 AF XY: 0.808 AC XY: 60105 AN XY: 74398

African (AFR) AF: 0.803 AC: 33308 AN: 41500

American (AMR) AF: 0.694 AC: 10599 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2834 AN: 3470

East Asian (EAS) AF: 0.703 AC: 3639 AN: 5176

South Asian (SAS) AF: 0.882 AC: 4249 AN: 4816

European-Finnish (FIN) AF: 0.865 AC: 9156 AN: 10590

Middle Eastern (MID) AF: 0.871 AC: 256 AN: 294

European-Non Finnish (NFE) AF: 0.827 AC: 56224 AN: 68000

Other (OTH) AF: 0.811 AC: 1710 AN: 2108

Alfa AF: 0.819 Hom.: 201043

Bravo AF: 0.788

Asia WGS AF: 0.791 AC: 2749 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive osteopetrosis 2 Benign:2

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jun 08, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.2
DANN	Benign	0.57
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs2277439; hg19: chr13-43155443; COSMIC: COSV53478399;