8-23197133-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003844.4(TNFRSF10A):c.1086G>C(p.Glu362Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,078 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TNFRSF10A
NM_003844.4 missense, splice_region

Scores

Splicing: ADA: 0.00004228

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.935

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.110568315).

BS2

High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF10A	NM_003844.4 linkuse as main transcript	c.1086G>C	p.Glu362Asp	missense_variant, splice_region_variant	9/10	ENST00000221132.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
TNFRSF10A	ENST00000221132.8 linkuse as main transcript	c.1086G>C	p.Glu362Asp	missense_variant, splice_region_variant	9/10	1	NM_003844.4	P1
TNFRSF10A	ENST00000613472.1 linkuse as main transcript	c.612G>C	p.Glu204Asp	missense_variant, splice_region_variant	8/9	1
TNFRSF10A	ENST00000519862.1 linkuse as main transcript	n.141G>C		splice_region_variant, non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152228

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461850

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 08, 2024

The c.1086G>C (p.E362D) alteration is located in exon 9 (coding exon 9) of the TNFRSF10A gene. This alteration results from a G to C substitution at nucleotide position 1086, causing the glutamic acid (E) at amino acid position 362 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.67

Cadd

Benign

3.5

Dann

Uncertain

0.98

DEOGEN2

Benign

0.0044

T;T

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.56

T;T

M_CAP

Benign

0.0094

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Uncertain

2.1

M;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.37

PROVEAN

Benign

-1.2

N;.

REVEL

Benign

0.075

Sift

Benign

0.43

T;.

Sift4G

Uncertain

0.059

T;T

Polyphen

0.98

D;.

Vest4

0.10

MutPred

0.39

Gain of phosphorylation at T361 (P = 0.1878);.;

MVP

0.28

MPC

0.078

ClinPred

0.25

GERP RS

-5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.036

gMVP

0.19

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000042

dbscSNV1_RF

Benign

0.024

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over