Genetic Variant TNFRSF10A:p.His141Arg (chr8-23202743-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_003844.4(TNFRSF10A):c.422A>G(p.His141Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,610,774 control chromosomes in the GnomAD database, including 203,964 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 0.45 ( 16833 hom., cov: 32)

Exomes 𝑓: 0.49 ( 187131 hom. )

Consequence

TNFRSF10A
NM_003844.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.99

Publications

50 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:

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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=7.9366896E-7).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF10A	NM_003844.4 link	c.422A>G	p.His141Arg	missense_variant	Exon 3 of 10	ENST00000221132.8	NP_003835.3	O00220

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFRSF10A	ENST00000221132.8 link	c.422A>G	p.His141Arg	missense_variant	Exon 3 of 10	1	NM_003844.4	ENSP00000221132.3	O00220
TNFRSF10A	ENST00000613472.1 link	c.32-84A>G		intron_variant	Intron 1 of 8	1		ENSP00000480778.1	F8U8C0
TNFRSF10A	ENST00000524158.5 link	c.-185A>G		5_prime_UTR_variant	Exon 3 of 7	5		ENSP00000428884.1	E5RFH1

Frequencies

GnomAD3 genomes

AF:

0.445

AC:

67660

AN:

151876

Hom.:

16823

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.460

Gnomad AMR

AF:

0.577

Gnomad ASJ

AF:

0.494

Gnomad EAS

AF:

0.976

Gnomad SAS

AF:

0.669

Gnomad FIN

AF:

0.404

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.463

Gnomad OTH

AF:

0.480

GnomAD2 exomes

AF:

0.536

AC:

134684

AN:

251356

AF XY:

0.537

show subpopulations

Gnomad AFR exome

AF:

0.281

Gnomad AMR exome

AF:

0.659

Gnomad ASJ exome

AF:

0.508

Gnomad EAS exome

AF:

0.977

Gnomad FIN exome

AF:

0.410

Gnomad NFE exome

AF:

0.460

Gnomad OTH exome

AF:

0.508

GnomAD4 exome

AF:

0.494

AC:

721238

AN:

1458780

Hom.:

187131

Cov.:

AF XY:

0.499

AC XY:

362266

AN XY:

725914

show subpopulations

African (AFR)

AF:

0.272

AC:

9103

AN:

33448

American (AMR)

AF:

0.646

AC:

28891

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.505

AC:

13181

AN:

26098

East Asian (EAS)

AF:

0.982

AC:

38970

AN:

39678

South Asian (SAS)

AF:

0.652

AC:

56185

AN:

86194

European-Finnish (FIN)

AF:

0.414

AC:

22078

AN:

53346

Middle Eastern (MID)

AF:

0.498

AC:

2867

AN:

5758

European-Non Finnish (NFE)

AF:

0.468

AC:

519573

AN:

1109286

Other (OTH)

AF:

0.504

AC:

30390

AN:

60264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

15191

30382

45573

60764

75955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15696

31392

47088

62784

78480

<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:

0.445

AC:

67695

AN:

151994

Hom.:

16833

Cov.:

AF XY:

0.452

AC XY:

33567

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.281

AC:

11632

AN:

41448

American (AMR)

AF:

0.577

AC:

8810

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.494

AC:

1713

AN:

3468

East Asian (EAS)

AF:

0.976

AC:

5053

AN:

5176

South Asian (SAS)

AF:

0.669

AC:

3217

AN:

4812

European-Finnish (FIN)

AF:

0.404

AC:

4267

AN:

10554

Middle Eastern (MID)

AF:

0.422

AC:

124

AN:

294

European-Non Finnish (NFE)

AF:

0.463

AC:

31441

AN:

67952

Other (OTH)

AF:

0.483

AC:

1019

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1782

3565

5347

7130

8912

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.461

Hom.:

66280

Bravo

AF:

0.450

TwinsUK

AF:

0.465

AC:

1724

ALSPAC

AF:

0.488

AC:

1879

ESP6500AA

AF:

0.284

AC:

1253

ESP6500EA

AF:

0.459

AC:

3950

ExAC

AF:

0.525

AC:

63784

Asia WGS

AF:

0.743

AC:

2581

AN:

3478

EpiCase

AF:

0.461

EpiControl

AF:

0.452

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.0050

(source)

DANN

Benign

0.24

DEOGEN2

Benign

0.0096

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.0057

LIST_S2

Benign

0.42

MetaRNN

Benign

7.9e-7

MetaSVM

Benign

-0.91

MutationAssessor

Benign

1.1

PhyloP100

-2.0

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.7

REVEL

Benign

0.043

Sift

Benign

0.42

Sift4G

Benign

0.20

Polyphen

0.82

Vest4

0.027

MPC

0.080

ClinPred

0.020

GERP RS

-7.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.032

gMVP

0.35

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over