rs346588

Variant names:

• chr13-42591332-A-G
• rs346588
• NM_003701.4:c.388-9420A>G

Variant summary

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

The NM_003701.4(TNFSF11):​c.388-9420A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 151,970 control chromosomes in the GnomAD database, including 2,198 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 0.16 (2198 hom., cov: 31)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.71
• Publications: 9 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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 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.388-9420A>G		intron	N/A	NP_003692.1	Q5T9Y4
	TNFSF11	NM_033012.4		c.169-9420A>G		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.388-9420A>G		intron	N/A	ENSP00000381775.3	O14788-1
	TNFSF11	ENST00000358545.6	TSL:1	c.169-9420A>G		intron	N/A	ENSP00000351347.2	O14788-2

Frequencies

GnomAD3 genomes AF: 0.158 AC: 23990 AN: 151852 Hom.: 2189 Cov.: 31

Gnomad AFR AF: 0.0817

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.154

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.118

Gnomad FIN AF: 0.134

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.172

Gnomad OTH AF: 0.163

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

GnomAD4 genome AF: 0.158 AC: 24013 AN: 151970 Hom.: 2198 Cov.: 31 AF XY: 0.157 AC XY: 11669 AN XY: 74284

African (AFR) AF: 0.0817 AC: 3389 AN: 41472

American (AMR) AF: 0.284 AC: 4342 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.154 AC: 534 AN: 3472

East Asian (EAS) AF: 0.296 AC: 1522 AN: 5142

South Asian (SAS) AF: 0.119 AC: 572 AN: 4812

European-Finnish (FIN) AF: 0.134 AC: 1416 AN: 10540

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

European-Non Finnish (NFE) AF: 0.172 AC: 11712 AN: 67948

Other (OTH) AF: 0.162 AC: 340 AN: 2104

Alfa AF: 0.179 Hom.: 454

Bravo AF: 0.170

Asia WGS AF: 0.201 AC: 699 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.0020
DANN	Benign	0.38
PhyloP100		-4.7
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: rs346588; hg19: chr13-43165468;