13-42574210-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003701.4(TNFSF11):c.-94C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0037 in 1,489,058 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0038 (18 hom.)
• Consequence: TNFSF11 NM_003701.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.542

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFSF11	NM_003701.4	c.-94C>T		5_prime_UTR_variant	1/5	ENST00000398795.7
TNFSF11	NM_033012.4	c.-1+2472C>T		intron_variant
TNFSF11	XM_047430707.1	c.-1+2472C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFSF11	ENST00000398795.7	c.-94C>T		5_prime_UTR_variant	1/5	1	NM_003701.4	P1
TNFSF11	ENST00000358545.6	c.-1+2472C>T		intron_variant		1

Frequencies

GnomAD3 genomes AF: 0.00275 AC: 418 AN: 152168 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00327

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0159

Gnomad NFE AF: 0.00381

Gnomad OTH AF: 0.00526

GnomAD4 exome AF: 0.00381 AC: 5096 AN: 1336778 Hom.: 18 Cov.: 28 AF XY: 0.00384 AC XY: 2541 AN XY: 661924

Gnomad4 AFR exome AF: 0.000431

Gnomad4 AMR exome AF: 0.00337

Gnomad4 ASJ exome AF: 0.0131

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000607

Gnomad4 FIN exome AF: 0.000993

Gnomad4 NFE exome AF: 0.00416

Gnomad4 OTH exome AF: 0.00437

GnomAD4 genome AF: 0.00274 AC: 417 AN: 152280 Hom.: 2 Cov.: 34 AF XY: 0.00223 AC XY: 166 AN XY: 74452

Gnomad4 AFR AF: 0.000698

Gnomad4 AMR AF: 0.00327

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00381

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00291 Hom.: 0

Bravo AF: 0.00284

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive osteopetrosis 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
Cadd	Benign	14
Dann	Benign	0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs199818393; hg19: chr13-43148346;