13-42573535-T-C

Variant names:

• chr13-42573535-T-C
• rs9533156
• ENST00000358545.6:c.-1+1797T>C

Variant summary

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

The ENST00000358545.6(TNFSF11):​c.-1+1797T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 152,020 control chromosomes in the GnomAD database, including 16,683 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 0.47 (16683 hom., cov: 32)
• Consequence: TNFSF11 ENST00000358545.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.67
• Publications: 45 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 (AFR) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF11	NM_033012.4	c.-1+1797T>C		intron_variant	Intron 3 of 6		NP_143026.1
TNFSF11	XM_047430707.1	c.-1+1797T>C		intron_variant	Intron 1 of 4		XP_047286663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF11	ENST00000358545.6	c.-1+1797T>C		intron_variant	Intron 3 of 6	1		ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70655 AN: 151902 Hom.: 16660 Cov.: 32

Gnomad AFR AF: 0.508

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.469

Gnomad SAS AF: 0.401

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.449

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

GnomAD4 genome AF: 0.465 AC: 70716 AN: 152020 Hom.: 16683 Cov.: 32 AF XY: 0.468 AC XY: 34769 AN XY: 74316

African (AFR) AF: 0.508 AC: 21066 AN: 41430

American (AMR) AF: 0.408 AC: 6243 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.322 AC: 1117 AN: 3470

East Asian (EAS) AF: 0.470 AC: 2432 AN: 5170

South Asian (SAS) AF: 0.400 AC: 1925 AN: 4810

European-Finnish (FIN) AF: 0.520 AC: 5495 AN: 10572

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.455 AC: 30960 AN: 67970

Other (OTH) AF: 0.446 AC: 940 AN: 2108

Alfa AF: 0.469 Hom.: 4532

Bravo AF: 0.459

Asia WGS AF: 0.432 AC: 1501 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.37
DANN	Benign	0.60
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9533156; hg19: chr13-43147671;