rs2200287

Variant names:

• chr13-42594524-G-A
• rs2200287
• NM_003701.4:c.388-6228G>A

Your query was ambiguous. Multiple possible variants found:

• chr13-42594524-G-A
• chr13-42594524-G-C
• chr13-42594524-G-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003701.4(TNFSF11):​c.388-6228G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 152,076 control chromosomes in the GnomAD database, including 9,812 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.35 (9812 hom., cov: 32)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 16 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF11	NM_003701.4	c.388-6228G>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.388-6228G>A		intron_variant	Intron 2 of 4	1	NM_003701.4	ENSP00000381775.3
TNFSF11	ENST00000358545.6	c.169-6228G>A		intron_variant	Intron 4 of 6	1		ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53850 AN: 151958 Hom.: 9806 Cov.: 32

Gnomad AFR AF: 0.330

Gnomad AMI AF: 0.354

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.502

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.373

Gnomad OTH AF: 0.377

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.354 AC: 53881 AN: 152076 Hom.: 9812 Cov.: 32 AF XY: 0.354 AC XY: 26346 AN XY: 74336

African (AFR) AF: 0.330 AC: 13688 AN: 41478

American (AMR) AF: 0.295 AC: 4512 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1857 AN: 3470

East Asian (EAS) AF: 0.217 AC: 1125 AN: 5190

South Asian (SAS) AF: 0.501 AC: 2415 AN: 4818

European-Finnish (FIN) AF: 0.345 AC: 3635 AN: 10540

Middle Eastern (MID) AF: 0.537 AC: 158 AN: 294

European-Non Finnish (NFE) AF: 0.373 AC: 25364 AN: 67976

Other (OTH) AF: 0.382 AC: 805 AN: 2108

Alfa AF: 0.372 Hom.: 28149

Bravo AF: 0.345

Asia WGS AF: 0.369 AC: 1285 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.6
DANN	Benign	0.51
PhyloP100		1.1
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: rs2200287; hg19: chr13-43168660;