rs9594782

Variant names:

• chr13-42577050-T-C
• rs9594782
• NM_003701.4:c.219+2528T>C

Variant summary

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

The NM_003701.4(TNFSF11):​c.219+2528T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0417 in 152,326 control chromosomes in the GnomAD database, including 182 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 0.042 (182 hom., cov: 33)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.693
• Publications: 14 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0849 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.219+2528T>C		intron	N/A	NP_003692.1	Q5T9Y4
	TNFSF11	NM_033012.4		c.1-4076T>C		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.219+2528T>C		intron	N/A	ENSP00000381775.3	O14788-1
	TNFSF11	ENST00000358545.6	TSL:1	c.1-4076T>C		intron	N/A	ENSP00000351347.2	O14788-2

Frequencies

GnomAD3 genomes AF: 0.0417 AC: 6342 AN: 152208 Hom.: 180 Cov.: 33

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.116

Gnomad EAS AF: 0.0919

Gnomad SAS AF: 0.0689

Gnomad FIN AF: 0.0301

Gnomad MID AF: 0.104

Gnomad NFE AF: 0.0492

Gnomad OTH AF: 0.0545

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

GnomAD4 genome AF: 0.0417 AC: 6347 AN: 152326 Hom.: 182 Cov.: 33 AF XY: 0.0410 AC XY: 3052 AN XY: 74486

African (AFR) AF: 0.0193 AC: 802 AN: 41562

American (AMR) AF: 0.0292 AC: 447 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.116 AC: 404 AN: 3468

East Asian (EAS) AF: 0.0917 AC: 476 AN: 5190

South Asian (SAS) AF: 0.0685 AC: 331 AN: 4832

European-Finnish (FIN) AF: 0.0301 AC: 320 AN: 10616

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0492 AC: 3348 AN: 68032

Other (OTH) AF: 0.0582 AC: 123 AN: 2114

Alfa AF: 0.0491 Hom.: 338

Bravo AF: 0.0398

Asia WGS AF: 0.0760 AC: 264 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.39
DANN	Benign	0.35
PhyloP100		-0.69
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: rs9594782; hg19: chr13-43151186;