chr13-42573888-T-C

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_033012.4(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 NM_033012.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.729

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF11	NM_033012.4	c.-1+2150T>C		intron_variant	Intron 3 of 6		NP_143026.1
TNFSF11	XM_047430707.1	c.-1+2150T>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+2150T>C		intron_variant	Intron 3 of 6	1		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

Gnomad4 AFR AF: 0.510

Gnomad4 AMR AF: 0.407

Gnomad4 ASJ AF: 0.322

Gnomad4 EAS AF: 0.473

Gnomad4 SAS AF: 0.393

Gnomad4 FIN AF: 0.520

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.444

Alfa AF: 0.447 Hom.: 16214

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	8.0
DANN	Benign	0.49

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs9525641; hg19: chr13-43148024;