13-42572346-G-C

Variant names:

• chr13-42572346-G-C
• rs7984870
• ENST00000358545.6:c.-1+608G>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+608G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 151,938 control chromosomes in the GnomAD database, including 16,171 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 0.46 (16171 hom., cov: 32)
• Consequence: TNFSF11 ENST00000358545.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.07
• Publications: 34 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000358545.6. 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_033012.4		c.-1+608G>C		intron	N/A	NP_143026.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF11	ENST00000358545.6	TSL:1	c.-1+608G>C		intron	N/A	ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.458 AC: 69608 AN: 151820 Hom.: 16148 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.405

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.444

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

GnomAD4 genome AF: 0.459 AC: 69671 AN: 151938 Hom.: 16171 Cov.: 32 AF XY: 0.461 AC XY: 34273 AN XY: 74282

African (AFR) AF: 0.486 AC: 20114 AN: 41402

American (AMR) AF: 0.405 AC: 6181 AN: 15274

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

East Asian (EAS) AF: 0.471 AC: 2433 AN: 5162

South Asian (SAS) AF: 0.395 AC: 1907 AN: 4822

European-Finnish (FIN) AF: 0.521 AC: 5503 AN: 10558

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

European-Non Finnish (NFE) AF: 0.456 AC: 30947 AN: 67934

Other (OTH) AF: 0.441 AC: 931 AN: 2112

Alfa AF: 0.460 Hom.: 2021

Bravo AF: 0.451

Asia WGS AF: 0.428 AC: 1488 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.33
DANN	Benign	0.66
PhyloP100		-1.1
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: rs7984870; hg19: chr13-43146482;