rs1054016

Variant names:

• chr13-42607866-G-T
• rs1054016
• NM_003701.4:c.*948G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003701.4(TNFSF11):​c.*948G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.354 in 151,648 control chromosomes in the GnomAD database, including 10,334 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.35 (10309 hom., cov: 32)
  • Exomes 𝑓: 0.41 (25 hom.)
• Consequence: TNFSF11 NM_003701.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.00600

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 13-42607866-G-T is Benign according to our data. Variant chr13-42607866-G-T is described in ClinVar as [Benign]. Clinvar id is 312251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF11	NM_003701.4	c.*948G>T		3_prime_UTR_variant	Exon 5 of 5	ENST00000398795.7	NP_003692.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF11	ENST00000398795.7	c.*948G>T		3_prime_UTR_variant	Exon 5 of 5	1	NM_003701.4	ENSP00000381775.3

Frequencies

GnomAD3 genomes AF: 0.354 AC: 53521 AN: 151008 Hom.: 10311 Cov.: 32

Gnomad AFR AF: 0.194

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.360

Gnomad ASJ AF: 0.306

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.329

Gnomad FIN AF: 0.488

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.361

GnomAD4 exome AF: 0.413 AC: 217 AN: 526 Hom.: 25 Cov.: 0 AF XY: 0.432 AC XY: 134 AN XY: 310

Gnomad4 EAS exome AF: 0.393

Gnomad4 FIN exome AF: 0.420

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.354 AC: 53522 AN: 151122 Hom.: 10309 Cov.: 32 AF XY: 0.358 AC XY: 26436 AN XY: 73802

Gnomad4 AFR AF: 0.194

Gnomad4 AMR AF: 0.360

Gnomad4 ASJ AF: 0.306

Gnomad4 EAS AF: 0.454

Gnomad4 SAS AF: 0.328

Gnomad4 FIN AF: 0.488

Gnomad4 NFE AF: 0.426

Gnomad4 OTH AF: 0.359

Alfa AF: 0.0794 Hom.: 195

Bravo AF: 0.341

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive osteopetrosis 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.6
DANN	Benign	0.49

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: rs1054016; hg19: chr13-43182002;