rs346574

Variant names:

• chr13-42606367-G-A
• rs346574
• NM_003701.4:c.533-130G>A

Variant summary

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

The NM_003701.4(TNFSF11):​c.533-130G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.065 in 1,114,984 control chromosomes in the GnomAD database, including 2,684 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 0.059 (274 hom., cov: 33)
  • Exomes 𝑓: 0.066 (2410 hom.)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.191
• Publications: 3 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=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0716 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.533-130G>A		intron	N/A	NP_003692.1	Q5T9Y4
	TNFSF11	NM_033012.4		c.314-130G>A		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.533-130G>A		intron	N/A	ENSP00000381775.3	O14788-1
	TNFSF11	ENST00000358545.6	TSL:1	c.314-130G>A		intron	N/A	ENSP00000351347.2	O14788-2

Frequencies

GnomAD3 genomes AF: 0.0590 AC: 8976 AN: 152146 Hom.: 274 Cov.: 33

Gnomad AFR AF: 0.0474

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0431

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0539

Gnomad FIN AF: 0.0878

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.0733

Gnomad OTH AF: 0.0540

GnomAD4 exome AF: 0.0660 AC: 63528 AN: 962720 Hom.: 2410 AF XY: 0.0652 AC XY: 32146 AN XY: 492724

African (AFR) AF: 0.0452 AC: 1028 AN: 22758

American (AMR) AF: 0.0267 AC: 930 AN: 34768

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 386 AN: 21214

East Asian (EAS) AF: 0.000317 AC: 11 AN: 34734

South Asian (SAS) AF: 0.0555 AC: 3713 AN: 66960

European-Finnish (FIN) AF: 0.0850 AC: 3726 AN: 43846

Middle Eastern (MID) AF: 0.0284 AC: 118 AN: 4162

European-Non Finnish (NFE) AF: 0.0738 AC: 50987 AN: 690656

Other (OTH) AF: 0.0603 AC: 2629 AN: 43622

GnomAD4 genome AF: 0.0590 AC: 8979 AN: 152264 Hom.: 274 Cov.: 33 AF XY: 0.0579 AC XY: 4309 AN XY: 74454

African (AFR) AF: 0.0475 AC: 1972 AN: 41552

American (AMR) AF: 0.0429 AC: 656 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5182

South Asian (SAS) AF: 0.0538 AC: 259 AN: 4816

European-Finnish (FIN) AF: 0.0878 AC: 931 AN: 10602

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.0733 AC: 4989 AN: 68020

Other (OTH) AF: 0.0534 AC: 113 AN: 2116

Alfa AF: 0.0680 Hom.: 51

Bravo AF: 0.0539

Asia WGS AF: 0.0240 AC: 87 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.81
DANN	Benign	0.81
PhyloP100		-0.19
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: rs346574; hg19: chr13-43180503;