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: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, ClinGen, Ambry Genetics, PanelApp Australia
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003701.4. 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
	TNFSF11	NM_003701.4	MANE Select	c.387+14G>A		intron	N/A	NP_003692.1	Q5T9Y4
	TNFSF11	NM_033012.4		c.168+14G>A		intron	N/A	NP_143026.1	O14788-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF11	ENST00000398795.7	TSL:1 MANE Select	c.387+14G>A		intron	N/A	ENSP00000381775.3	O14788-1
	TNFSF11	ENST00000358545.6	TSL:1	c.168+14G>A		intron	N/A	ENSP00000351347.2	O14788-2

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Autosomal recessive osteopetrosis 2 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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;