13-42589663-G-C

Variant names:

• chr13-42589663-G-C
• rs2148073
• NM_003701.4:c.387+8370G>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.387+8370G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.795 in 152,092 control chromosomes in the GnomAD database, including 48,318 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 0.80 (48318 hom., cov: 31)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.185
• 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: 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=-0.91).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.859 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF11	NM_003701.4	MANE Select	c.387+8370G>C		intron	N/A	NP_003692.1
	TNFSF11	NM_033012.4		c.168+8370G>C		intron	N/A	NP_143026.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF11	ENST00000398795.7	TSL:1 MANE Select	c.387+8370G>C		intron	N/A	ENSP00000381775.3
	TNFSF11	ENST00000358545.6	TSL:1	c.168+8370G>C		intron	N/A	ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.795 AC: 120871 AN: 151974 Hom.: 48287 Cov.: 31

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.828

Gnomad AMR AF: 0.693

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.882

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.826

Gnomad OTH AF: 0.800

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

GnomAD4 genome AF: 0.795 AC: 120947 AN: 152092 Hom.: 48318 Cov.: 31 AF XY: 0.797 AC XY: 59270 AN XY: 74348

African (AFR) AF: 0.764 AC: 31662 AN: 41466

American (AMR) AF: 0.692 AC: 10571 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.817 AC: 2836 AN: 3472

East Asian (EAS) AF: 0.704 AC: 3628 AN: 5156

South Asian (SAS) AF: 0.881 AC: 4238 AN: 4812

European-Finnish (FIN) AF: 0.865 AC: 9172 AN: 10600

Middle Eastern (MID) AF: 0.867 AC: 255 AN: 294

European-Non Finnish (NFE) AF: 0.826 AC: 56137 AN: 67984

Other (OTH) AF: 0.802 AC: 1693 AN: 2110

Alfa AF: 0.804 Hom.: 5768

Bravo AF: 0.776

Asia WGS AF: 0.791 AC: 2750 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.6
DANN	Benign	0.38
PhyloP100		0.18
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: rs2148073; hg19: chr13-43163799;