Genetic Variant TNFRSF10A:p.His141Arg (chr8-23202743-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_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. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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

GnomAD3 exomes

AF:

0.536

AC:

134684

AN:

251356

Hom.:

39581

AF XY:

0.537

AC XY:

72971

AN XY:

135820

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 SAS exome

AF:

0.654

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

Gnomad4 AFR exome

AF:

0.272

Gnomad4 AMR exome

AF:

0.646

Gnomad4 ASJ exome

AF:

0.505

Gnomad4 EAS exome

AF:

0.982

Gnomad4 SAS exome

AF:

0.652

Gnomad4 FIN exome

AF:

0.414

Gnomad4 NFE exome

AF:

0.468

Gnomad4 OTH exome

AF:

0.504

GnomAD4 genome

AF:

0.445

AC:

67695

AN:

151994

Hom.:

16833

Cov.:

AF XY:

0.452

AC XY:

33567

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.281

Gnomad4 AMR

AF:

0.577

Gnomad4 ASJ

AF:

0.494

Gnomad4 EAS

AF:

0.976

Gnomad4 SAS

AF:

0.669

Gnomad4 FIN

AF:

0.404

Gnomad4 NFE

AF:

0.463

Gnomad4 OTH

AF:

0.483

Alfa

AF:

0.471

Hom.:

35506

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

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

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

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