ENST00000358545.6:c.-1+2150T>C

Variant names:

• chr13-42573888-T-C
• rs9525641
• ENST00000358545.6:c.-1+2150T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The ENST00000358545.6(TNFSF11):​c.-1+2150T>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 152,036 control chromosomes in the GnomAD database, including 16,685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.47 (16685 hom., cov: 31)
• Consequence: TNFSF11 ENST00000358545.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.729
• Publications: 39 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 13-42573888-T-C is Benign according to our data. Variant chr13-42573888-T-C is described in ClinVar as Benign. ClinVar VariationId is 1297311.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.504 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+2150T>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+2150T>C		intron	N/A	ENSP00000351347.2

Frequencies

GnomAD3 genomes AF: 0.465 AC: 70685 AN: 151918 Hom.: 16659 Cov.: 31

Gnomad AFR AF: 0.510

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.407

Gnomad ASJ AF: 0.322

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.394

Gnomad FIN AF: 0.520

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.447

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

GnomAD4 genome AF: 0.465 AC: 70752 AN: 152036 Hom.: 16685 Cov.: 31 AF XY: 0.468 AC XY: 34784 AN XY: 74330

African (AFR) AF: 0.510 AC: 21145 AN: 41444

American (AMR) AF: 0.407 AC: 6218 AN: 15284

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

East Asian (EAS) AF: 0.473 AC: 2446 AN: 5174

South Asian (SAS) AF: 0.393 AC: 1890 AN: 4814

European-Finnish (FIN) AF: 0.520 AC: 5510 AN: 10586

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

European-Non Finnish (NFE) AF: 0.456 AC: 30950 AN: 67946

Other (OTH) AF: 0.444 AC: 938 AN: 2112

Alfa AF: 0.451 Hom.: 22708

Bravo AF: 0.459

Asia WGS AF: 0.427 AC: 1485 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 19131500, 18502820)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.0
DANN	Benign	0.49
PhyloP100		0.73
PromoterAI		0.029	Neutral
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: rs9525641; hg19: chr13-43148024;