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

Variant summary

Our verdict is Benign. The variant received -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

Publications

75 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005118.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF15	NM_005118.4	MANE Select	c.302-63A>G		intron	N/A	NP_005109.2
	TNFSF15	NM_001204344.1		c.125-63A>G		intron	N/A	NP_001191273.1	O95150-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFSF15	ENST00000374045.5	TSL:1 MANE Select	c.302-63A>G		intron	N/A	ENSP00000363157.3	O95150-1
	TNFSF15	ENST00000374044.1	TSL:6	c.8A>G	p.His3Arg	missense	Exon 1 of 1	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

GnomAD2 exomes

AF:

0.761

AC:

170804

AN:

224406

AF XY:

0.754

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 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

African (AFR)

AF:

0.937

AC:

29396

AN:

31362

American (AMR)

AF:

0.820

AC:

33713

AN:

41114

Ashkenazi Jewish (ASJ)

AF:

0.755

AC:

18649

AN:

24688

East Asian (EAS)

AF:

0.683

AC:

26662

AN:

39050

South Asian (SAS)

AF:

0.767

AC:

62992

AN:

82086

European-Finnish (FIN)

AF:

0.807

AC:

42498

AN:

52642

Middle Eastern (MID)

AF:

0.761

AC:

4213

AN:

5538

European-Non Finnish (NFE)

AF:

0.715

AC:

752346

AN:

1052922

Other (OTH)

AF:

0.745

AC:

42890

AN:

57576

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

13849

27698

41547

55396

69245

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18708

37416

56124

74832

93540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.790

AC:

120173

AN:

152142

Hom.:

48111

Cov.:

AF XY:

0.794

AC XY:

59025

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.929

AC:

38566

AN:

41532

American (AMR)

AF:

0.791

AC:

12110

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.759

AC:

2631

AN:

3468

East Asian (EAS)

AF:

0.649

AC:

3354

AN:

5164

South Asian (SAS)

AF:

0.773

AC:

3719

AN:

4812

European-Finnish (FIN)

AF:

0.808

AC:

8553

AN:

10586

Middle Eastern (MID)

AF:

0.748

AC:

220

AN:

294

European-Non Finnish (NFE)

AF:

0.716

AC:

48687

AN:

67964

Other (OTH)

AF:

0.756

AC:

1595

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1231

2461

3692

4922

6153

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

864

1728

2592

3456

4320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.751

Hom.:

84947

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.15

(source)

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

PhyloP100

-0.67

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

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over