NM_003701.4:c.387+4496G>A

Variant names:

• chr13-42585789-G-A
• rs9525645
• NM_003701.4:c.387+4496G>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.387+4496G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.807 in 152,186 control chromosomes in the GnomAD database, including 49,795 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 0.81 (49795 hom., cov: 32)
• Consequence: TNFSF11 NM_003701.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0980
• 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: 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=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF11	NM_003701.4	c.387+4496G>A		intron_variant	Intron 2 of 4	ENST00000398795.7	NP_003692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF11	ENST00000398795.7	c.387+4496G>A		intron_variant	Intron 2 of 4	1	NM_003701.4	ENSP00000381775.3
TNFSF11	ENST00000358545.6	c.168+4496G>A		intron_variant	Intron 4 of 6	1		ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.808 AC: 122805 AN: 152068 Hom.: 49763 Cov.: 32

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.802

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.817

Gnomad EAS AF: 0.702

Gnomad SAS AF: 0.882

Gnomad FIN AF: 0.865

Gnomad MID AF: 0.854

Gnomad NFE AF: 0.827

Gnomad OTH AF: 0.809

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

GnomAD4 genome AF: 0.807 AC: 122886 AN: 152186 Hom.: 49795 Cov.: 32 AF XY: 0.809 AC XY: 60183 AN XY: 74398

African (AFR) AF: 0.806 AC: 33453 AN: 41516

American (AMR) AF: 0.694 AC: 10620 AN: 15298

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

East Asian (EAS) AF: 0.703 AC: 3638 AN: 5174

South Asian (SAS) AF: 0.881 AC: 4251 AN: 4824

European-Finnish (FIN) AF: 0.865 AC: 9163 AN: 10588

Middle Eastern (MID) AF: 0.874 AC: 257 AN: 294

European-Non Finnish (NFE) AF: 0.827 AC: 56223 AN: 67994

Other (OTH) AF: 0.811 AC: 1714 AN: 2114

Alfa AF: 0.817 Hom.: 9970

Bravo AF: 0.790

Asia WGS AF: 0.791 AC: 2749 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.19
PhyloP100		0.098
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: rs9525645; hg19: chr13-43159925;