rs2277439

Positions:

• chr13-42581307-G-A

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 195202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-42581307-G-A is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
TNFSF11	NM_003701.4	c.387+14G>A		intron_variant		ENST00000398795.7	NP_003692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFSF11	ENST00000398795.7	c.387+14G>A		intron_variant		1	NM_003701.4	ENSP00000381775.3
TNFSF11	ENST00000358545.6	c.168+14G>A		intron_variant		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

GnomAD3 exomes AF: 0.801 AC: 200955 AN: 250922 Hom.: 81386 AF XY: 0.812 AC XY: 110235 AN XY: 135722

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 SAS exome AF: 0.886

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

Gnomad4 AFR exome AF: 0.807

Gnomad4 AMR exome AF: 0.628

Gnomad4 ASJ exome AF: 0.821

Gnomad4 EAS exome AF: 0.673

Gnomad4 SAS exome AF: 0.884

Gnomad4 FIN exome AF: 0.869

Gnomad4 NFE exome AF: 0.828

Gnomad4 OTH exome AF: 0.819

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

Gnomad4 AFR AF: 0.803

Gnomad4 AMR AF: 0.694

Gnomad4 ASJ AF: 0.817

Gnomad4 EAS AF: 0.703

Gnomad4 SAS AF: 0.882

Gnomad4 FIN AF: 0.865

Gnomad4 NFE AF: 0.827

Gnomad4 OTH AF: 0.811

Alfa AF: 0.824 Hom.: 89096

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Autosomal recessive osteopetrosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 08, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	8.2
DANN	Benign	0.57

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