rs2200287

chr13-42594524-G-Achr13-42594524-G-Cchr13-42594524-G-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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/exons	MANE	UniProt
TNFSF11	NM_003701.4	c.388-6228G>A		intron_variant		ENST00000398795.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF11	ENST00000398795.7	c.388-6228G>A		intron_variant		1	NM_003701.4	P1
TNFSF11	ENST00000358545.6	c.169-6228G>A		intron_variant		1

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

Gnomad4 AFR AF: 0.330

Gnomad4 AMR AF: 0.295

Gnomad4 ASJ AF: 0.535

Gnomad4 EAS AF: 0.217

Gnomad4 SAS AF: 0.501

Gnomad4 FIN AF: 0.345

Gnomad4 NFE AF: 0.373

Gnomad4 OTH AF: 0.382

Alfa AF: 0.385 Hom.: 12748

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

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: rs2200287; hg19: chr13-43168660;