NM_003701.4:c.387+14G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003701.4(TNFSF11):c.387+14G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.82 in 1,613,398 control chromosomes in the GnomAD database, including 544,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.81 ( 49680 hom., cov: 31)

Exomes 𝑓: 0.82 ( 494565 hom. )

Consequence

TNFSF11
NM_003701.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.49

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.81).

BP6

Variant 13-42581307-G-A is Benign according to our data. Variant chr13-42581307-G-A is described in ClinVar as [Benign]. Clinvar id is 195202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-42581307-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.86 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF11	NM_003701.4 link	c.387+14G>A		intron_variant	Intron 2 of 4	ENST00000398795.7	NP_003692.1	O14788-1Q5T9Y4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF11	ENST00000398795.7 link	c.387+14G>A		intron_variant	Intron 2 of 4	1	NM_003701.4	ENSP00000381775.3		O14788-1
TNFSF11	ENST00000358545.6 link	c.168+14G>A		intron_variant	Intron 4 of 6	1		ENSP00000351347.2		O14788-2

Frequencies

GnomAD3 genomes

AF:

0.807

AC:

122624

AN:

152028

Hom.:

49646

Cov.:

show subpopulations

Gnomad AFR

AF:

0.803

Gnomad AMI

AF:

0.802

Gnomad AMR

AF:

0.695

Gnomad ASJ

AF:

0.817

Gnomad EAS

AF:

0.702

Gnomad SAS

AF:

0.883

Gnomad FIN

AF:

0.865

Gnomad MID

AF:

0.851

Gnomad NFE

AF:

0.827

Gnomad OTH

AF:

0.809

GnomAD3 exomes

AF:

0.801

AC:

200955

AN:

250922

Hom.:

81386

AF XY:

0.812

AC XY:

110235

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.806

Gnomad AMR exome

AF:

0.623

Gnomad ASJ exome

AF:

0.819

Gnomad EAS exome

AF:

0.695

Gnomad SAS exome

AF:

0.886

Gnomad FIN exome

AF:

0.871

Gnomad NFE exome

AF:

0.833

Gnomad OTH exome

AF:

0.813

GnomAD4 exome

AF:

0.821

AC:

1200085

AN:

1461252

Hom.:

494565

Cov.:

AF XY:

0.824

AC XY:

599325

AN XY:

726956

show subpopulations

Gnomad4 AFR exome

AF:

0.807

Gnomad4 AMR exome

AF:

0.628

Gnomad4 ASJ exome

AF:

0.821

Gnomad4 EAS exome

AF:

0.673

Gnomad4 SAS exome

AF:

0.884

Gnomad4 FIN exome

AF:

0.869

Gnomad4 NFE exome

AF:

0.828

Gnomad4 OTH exome

AF:

0.819

GnomAD4 genome

AF:

0.807

AC:

122706

AN:

152146

Hom.:

49680

Cov.:

AF XY:

0.808

AC XY:

60105

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.803

Gnomad4 AMR

AF:

0.694

Gnomad4 ASJ

AF:

0.817

Gnomad4 EAS

AF:

0.703

Gnomad4 SAS

AF:

0.882

Gnomad4 FIN

AF:

0.865

Gnomad4 NFE

AF:

0.827

Gnomad4 OTH

AF:

0.811

Alfa

AF:

0.824

Hom.:

89096

Bravo

AF:

0.788

Asia WGS

AF:

0.791

AC:

2749

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Autosomal recessive osteopetrosis 2

Benign:2

Jan 12, 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. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Jun 08, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

8.2

DANN

Benign

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over