Genetic Variant TNFRSF10A:p.Val99Phe (chr8-23224767-C-A) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003844.4(TNFRSF10A):c.295G>T(p.Val99Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000232 in 1,566,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

TNFRSF10A
NM_003844.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.110

Publications

4 publications found

Variant links:

Genes affected

TNFRSF10A (HGNC:11904): (TNF receptor superfamily member 10a) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL), and thus transduces cell death signal and induces cell apoptosis. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. [provided by RefSeq, Jul 2008]

TNFRSF10A links:

TNFRSF10A-DT (HGNC:52647): (TNFRSF10A divergent transcript)

TNFRSF10A-DT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.17915294).

BS2

High AC in GnomAd4 at 24 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003844.4. 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
	TNFRSF10A	NM_003844.4	MANE Select	c.295G>T	p.Val99Phe	missense	Exon 1 of 10	NP_003835.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF10A	ENST00000221132.8	TSL:1 MANE Select	c.295G>T	p.Val99Phe	missense	Exon 1 of 10	ENSP00000221132.3	O00220
TNFRSF10A	ENST00000613472.1	TSL:1	c.31+264G>T		intron	N/A	ENSP00000480778.1	F8U8C0
TNFRSF10A	ENST00000901503.1		c.295G>T	p.Val99Phe	missense	Exon 1 of 9	ENSP00000571562.1

Frequencies

GnomAD3 genomes

AF:

0.000158

AC:

AN:

152026

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000117

AC:

AN:

171364

AF XY:

0.0000868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000289

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000240

AC:

339

AN:

1414728

Hom.:

Cov.:

AF XY:

0.000230

AC XY:

161

AN XY:

699180

show subpopulations

African (AFR)

AF:

0.0000306

AC:

AN:

32632

American (AMR)

AF:

0.00

AC:

AN:

36972

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25208

East Asian (EAS)

AF:

0.00

AC:

AN:

37714

South Asian (SAS)

AF:

0.00

AC:

AN:

80504

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49682

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5402

European-Non Finnish (NFE)

AF:

0.000306

AC:

333

AN:

1088028

Other (OTH)

AF:

0.0000853

AC:

AN:

58586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

101

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000158

AC:

AN:

152026

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74262

show subpopulations

African (AFR)

AF:

0.000145

AC:

AN:

41422

American (AMR)

AF:

0.00

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000178

Hom.:

Bravo

AF:

0.000121

ExAC

AF:

0.0000515

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.21

CADD

Benign

6.3

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.010

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.86

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.50

M_CAP

Benign

0.014

MetaRNN

Benign

0.18

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.3

PhyloP100

-0.11

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.36

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0030

Polyphen

0.99

Vest4

0.28

MVP

0.55

MPC

0.088

ClinPred

0.086

GERP RS

0.30

PromoterAI

0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.084

gMVP

0.24

Mutation Taster

=100/0

polymorphism

(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