Genetic Variant TNFSF10:p.Asp47Glu (chr3-172514990-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003810.4(TNFSF10):c.141C>A(p.Asp47Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00656 in 1,614,012 control chromosomes in the GnomAD database, including 438 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.030 ( 242 hom., cov: 32)

Exomes 𝑓: 0.0041 ( 196 hom. )

Consequence

TNFSF10
NM_003810.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.393

Publications

18 publications found

Variant links:

Genes affected

TNFSF10 (HGNC:11925): (TNF superfamily member 10) The protein encoded by this gene is a cytokine that belongs to the tumor necrosis factor (TNF) ligand family. This protein preferentially induces apoptosis in transformed and tumor cells, but does not appear to kill normal cells although it is expressed at a significant level in most normal tissues. This protein binds to several members of TNF receptor superfamily including TNFRSF10A/TRAILR1, TNFRSF10B/TRAILR2, TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and possibly also to TNFRSF11B/OPG. The activity of this protein may be modulated by binding to the decoy receptors TNFRSF10C/TRAILR3, TNFRSF10D/TRAILR4, and TNFRSF11B/OPG that cannot induce apoptosis. The binding of this protein to its receptors has been shown to trigger the activation of MAPK8/JNK, caspase 8, and caspase 3. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2010]

TNFSF10 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=0.0012619793).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.1 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003810.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFSF10	NM_003810.4	MANE Select	c.141C>A	p.Asp47Glu	missense	Exon 2 of 5	NP_003801.1	Q6IBA9
TNFSF10	NM_001190942.2		c.141C>A	p.Asp47Glu	missense	Exon 2 of 3	NP_001177871.1	P50591-2
TNFSF10	NR_033994.2		n.187C>A		non_coding_transcript_exon	Exon 2 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFSF10	ENST00000241261.7	TSL:1 MANE Select	c.141C>A	p.Asp47Glu	missense	Exon 2 of 5	ENSP00000241261.2	P50591-1
TNFSF10	ENST00000420541.6	TSL:1	c.141C>A	p.Asp47Glu	missense	Exon 2 of 3	ENSP00000389931.2	P50591-2
TNFSF10	ENST00000855872.1		c.141C>A	p.Asp47Glu	missense	Exon 2 of 6	ENSP00000525931.1

Frequencies

GnomAD3 genomes

AF:

0.0305

AC:

4632

AN:

152070

Hom.:

241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.103

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0128

Gnomad ASJ

AF:

0.0127

Gnomad EAS

AF:

0.00116

Gnomad SAS

AF:

0.0108

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.0177

GnomAD2 exomes

AF:

0.00989

AC:

2486

AN:

251310

AF XY:

0.00763

show subpopulations

Gnomad AFR exome

AF:

0.105

Gnomad AMR exome

AF:

0.00674

Gnomad ASJ exome

AF:

0.0133

Gnomad EAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000836

Gnomad OTH exome

AF:

0.00570

GnomAD4 exome

AF:

0.00407

AC:

5951

AN:

1461824

Hom.:

196

Cov.:

AF XY:

0.00376

AC XY:

2735

AN XY:

727224

show subpopulations

African (AFR)

AF:

0.0992

AC:

3319

AN:

33470

American (AMR)

AF:

0.00725

AC:

324

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0134

AC:

351

AN:

26134

East Asian (EAS)

AF:

0.000705

AC:

AN:

39700

South Asian (SAS)

AF:

0.00800

AC:

690

AN:

86258

European-Finnish (FIN)

AF:

0.0000374

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0177

AC:

102

AN:

5766

European-Non Finnish (NFE)

AF:

0.000532

AC:

592

AN:

1111972

Other (OTH)

AF:

0.00899

AC:

543

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

292

585

877

1170

1462

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

136

272

408

544

680

<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:

0.0305

AC:

4641

AN:

152188

Hom.:

242

Cov.:

AF XY:

0.0288

AC XY:

2146

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.103

AC:

4258

AN:

41490

American (AMR)

AF:

0.0128

AC:

195

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0127

AC:

AN:

3468

East Asian (EAS)

AF:

0.00116

AC:

AN:

5182

South Asian (SAS)

AF:

0.0108

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10600

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68014

Other (OTH)

AF:

0.0184

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

206

412

619

825

1031

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<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:

0.00914

Hom.:

168

Bravo

AF:

0.0345

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0980

AC:

432

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.0116

AC:

1407

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.000763

EpiControl

AF:

0.00119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.17

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.64

MetaRNN

Benign

0.0013

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

0.39

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.050

REVEL

Benign

0.037

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.012

MutPred

0.11

Gain of ubiquitination at K43 (P = 0.0628)

MPC

0.054

ClinPred

0.0027

GERP RS

-1.5

Varity_R

0.034

gMVP

0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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