rs2277438

Positions:

• chr13-42581032-G-A
• chr13-42581032-G-C

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.220-94G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 1,337,336 control chromosomes in the GnomAD database, including 449,893 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.81 (49688 hom., cov: 32)
  • Exomes 𝑓: 0.82 (400205 hom.)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.40

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=-0.91).
• BP6: Variant 13-42581032-G-A is Benign according to our data. Variant chr13-42581032-G-A is described in ClinVar as [Benign]. Clinvar id is 1183681.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/exons	MANE	Protein	UniProt
TNFSF11	NM_003701.4	c.220-94G>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.220-94G>A		intron_variant		1	NM_003701.4	ENSP00000381775	P1
TNFSF11	ENST00000358545.6	c.1-94G>A		intron_variant		1		ENSP00000351347

Frequencies

GnomAD3 genomes AF: 0.807 AC: 122660 AN: 152076 Hom.: 49654 Cov.: 32

Gnomad AFR AF: 0.802

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.883

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.850

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.808

GnomAD4 exome AF: 0.820 AC: 971627 AN: 1185142 Hom.: 400205 AF XY: 0.824 AC XY: 496768 AN XY: 603196

Gnomad4 AFR exome AF: 0.806

Gnomad4 AMR exome AF: 0.628

Gnomad4 ASJ exome AF: 0.821

Gnomad4 EAS exome AF: 0.672

Gnomad4 SAS exome AF: 0.884

Gnomad4 FIN exome AF: 0.869

Gnomad4 NFE exome AF: 0.828

Gnomad4 OTH exome AF: 0.818

GnomAD4 genome AF: 0.806 AC: 122742 AN: 152194 Hom.: 49688 Cov.: 32 AF XY: 0.808 AC XY: 60118 AN XY: 74402

Gnomad4 AFR AF: 0.802

Gnomad4 AMR AF: 0.694

Gnomad4 ASJ AF: 0.817

Gnomad4 EAS AF: 0.704

Gnomad4 SAS AF: 0.882

Gnomad4 FIN AF: 0.865

Gnomad4 NFE AF: 0.827

Gnomad4 OTH AF: 0.810

Alfa AF: 0.771 Hom.: 2396

Bravo AF: 0.788

Asia WGS AF: 0.791 AC: 2749 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.9
DANN	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2277438; hg19: chr13-43155168; COSMIC: COSV53476884;