Genetic Variant TNFSF15:c.302-63A>G (chr9-114790969-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_005118.4(TNFSF15):c.302-63A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.736 in 1,539,120 control chromosomes in the GnomAD database, including 419,605 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.79 ( 48111 hom., cov: 31)

Exomes 𝑓: 0.73 ( 371494 hom. )

Consequence

TNFSF15
NM_005118.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.671

Variant links:

Genes affected

TNFSF15 (HGNC:11931): (TNF superfamily member 15) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein is abundantly expressed in endothelial cells, but is not expressed in either B or T cells. The expression of this protein is inducible by TNF and IL-1 alpha. This cytokine is a ligand for receptor TNFRSF25 and decoy receptor TNFRSF21/DR6. It can activate NF-kappaB and MAP kinases, and acts as an autocrine factor to induce apoptosis in endothelial cells. This cytokine is also found to inhibit endothelial cell proliferation, and thus may function as an angiogenesis inhibitor. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Feb 2011]

TNFSF15 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=8.2134983E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFSF15	NM_005118.4 link	c.302-63A>G		intron_variant	Intron 3 of 3	ENST00000374045.5	NP_005109.2	O95150-1A0A0U5JA19
TNFSF15	NM_001204344.1 link	c.125-63A>G		intron_variant	Intron 1 of 1		NP_001191273.1	O95150-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFSF15	ENST00000374045.5 link	c.302-63A>G		intron_variant	Intron 3 of 3	1	NM_005118.4	ENSP00000363157.3		O95150-1
TNFSF15	ENST00000374044.1 link	c.8A>G	p.His3Arg	missense_variant	Exon 1 of 1	6		ENSP00000363156.1		X6R8I9

Frequencies

GnomAD3 genomes

AF:

0.790

AC:

120037

AN:

152024

Hom.:

48036

Cov.:

show subpopulations

Gnomad AFR

AF:

0.928

Gnomad AMI

AF:

0.811

Gnomad AMR

AF:

0.791

Gnomad ASJ

AF:

0.759

Gnomad EAS

AF:

0.649

Gnomad SAS

AF:

0.771

Gnomad FIN

AF:

0.808

Gnomad MID

AF:

0.753

Gnomad NFE

AF:

0.716

Gnomad OTH

AF:

0.755

GnomAD3 exomes

AF:

0.761

AC:

170804

AN:

224406

Hom.:

65387

AF XY:

0.754

AC XY:

91735

AN XY:

121682

show subpopulations

Gnomad AFR exome

AF:

0.933

Gnomad AMR exome

AF:

0.829

Gnomad ASJ exome

AF:

0.755

Gnomad EAS exome

AF:

0.629

Gnomad SAS exome

AF:

0.762

Gnomad FIN exome

AF:

0.813

Gnomad NFE exome

AF:

0.727

Gnomad OTH exome

AF:

0.739

GnomAD4 exome

AF:

0.731

AC:

1013359

AN:

1386978

Hom.:

371494

Cov.:

AF XY:

0.731

AC XY:

505109

AN XY:

691204

show subpopulations

Gnomad4 AFR exome

AF:

0.937

Gnomad4 AMR exome

AF:

0.820

Gnomad4 ASJ exome

AF:

0.755

Gnomad4 EAS exome

AF:

0.683

Gnomad4 SAS exome

AF:

0.767

Gnomad4 FIN exome

AF:

0.807

Gnomad4 NFE exome

AF:

0.715

Gnomad4 OTH exome

AF:

0.745

GnomAD4 genome

AF:

0.790

AC:

120173

AN:

152142

Hom.:

48111

Cov.:

AF XY:

0.794

AC XY:

59025

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.929

Gnomad4 AMR

AF:

0.791

Gnomad4 ASJ

AF:

0.759

Gnomad4 EAS

AF:

0.649

Gnomad4 SAS

AF:

0.773

Gnomad4 FIN

AF:

0.808

Gnomad4 NFE

AF:

0.716

Gnomad4 OTH

AF:

0.756

Alfa

AF:

0.751

Hom.:

18847

Bravo

AF:

0.791

TwinsUK

AF:

0.706

AC:

2616

ALSPAC

AF:

0.704

AC:

2713

ExAC

AF:

0.751

AC:

90787

Asia WGS

AF:

0.774

AC:

2689

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.15

DANN

Benign

0.72

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.19

MetaRNN

Benign

8.2e-7

MetaSVM

Benign

-1.0

PROVEAN

Benign

-0.28

REVEL

Benign

0.0

Sift

Benign

1.0

Sift4G

Benign

1.0

Vest4

0.021

ClinPred

0.0032

GERP RS

-4.2

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over