rs1047266

chr8-23043188-G-Achr8-23043188-G-Cchr8-23043188-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003842.5(TNFRSF10B):c.200C>T(p.Ala67Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0757 in 1,613,848 control chromosomes in the GnomAD database, including 6,251 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.069 (610 hom., cov: 32)
  • Exomes 𝑓: 0.076 (5641 hom.)
• Consequence: TNFRSF10B NM_003842.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.151

Genes affected

TNFRSF10B (HGNC:11905): (TNF receptor superfamily member 10b) The protein encoded by this gene is a member of the TNF-receptor superfamily, and contains an intracellular death domain. This receptor can be activated by tumor necrosis factor-related apoptosis inducing ligand (TNFSF10/TRAIL/APO-2L), and transduces an apoptosis signal. Studies with FADD-deficient mice suggested that FADD, a death domain containing adaptor protein, is required for the apoptosis mediated by this protein. Two transcript variants encoding different isoforms and one non-coding transcript have been found for this gene. [provided by RefSeq, Mar 2009]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005087942).
• BP6: Variant 8-23043188-G-A is Benign according to our data. Variant chr8-23043188-G-A is described in ClinVar as [Benign]. Clinvar id is 3056241.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF10B	NM_003842.5	c.200C>T	p.Ala67Val	missense_variant	2/9	ENST00000276431.9
TNFRSF10B	NM_147187.3	c.200C>T	p.Ala67Val	missense_variant	2/10
TNFRSF10B	NR_027140.2	n.282-12316C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF10B	ENST00000276431.9	c.200C>T	p.Ala67Val	missense_variant	2/9	1	NM_003842.5	P2

Frequencies

GnomAD3 genomes AF: 0.0694 AC: 10547 AN: 152016 Hom.: 612 Cov.: 32

Gnomad AFR AF: 0.0166

Gnomad AMI AF: 0.0800

Gnomad AMR AF: 0.130

Gnomad ASJ AF: 0.0671

Gnomad EAS AF: 0.291

Gnomad SAS AF: 0.0402

Gnomad FIN AF: 0.0822

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0712

Gnomad OTH AF: 0.0722

GnomAD3 exomes AF: 0.0967 AC: 24279 AN: 251018 Hom.: 1923 AF XY: 0.0902 AC XY: 12245 AN XY: 135680

Gnomad AFR exome AF: 0.0143

Gnomad AMR exome AF: 0.188

Gnomad ASJ exome AF: 0.0670

Gnomad EAS exome AF: 0.300

Gnomad SAS exome AF: 0.0377

Gnomad FIN exome AF: 0.0816

Gnomad NFE exome AF: 0.0699

Gnomad OTH exome AF: 0.0846

GnomAD4 exome AF: 0.0764 AC: 111663 AN: 1461714 Hom.: 5641 Cov.: 31 AF XY: 0.0748 AC XY: 54399 AN XY: 727154

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.180

Gnomad4 ASJ exome AF: 0.0670

Gnomad4 EAS exome AF: 0.271

Gnomad4 SAS exome AF: 0.0386

Gnomad4 FIN exome AF: 0.0827

Gnomad4 NFE exome AF: 0.0700

Gnomad4 OTH exome AF: 0.0834

GnomAD4 genome AF: 0.0693 AC: 10544 AN: 152134 Hom.: 610 Cov.: 32 AF XY: 0.0704 AC XY: 5237 AN XY: 74366

Gnomad4 AFR AF: 0.0166

Gnomad4 AMR AF: 0.130

Gnomad4 ASJ AF: 0.0671

Gnomad4 EAS AF: 0.290

Gnomad4 SAS AF: 0.0400

Gnomad4 FIN AF: 0.0822

Gnomad4 NFE AF: 0.0712

Gnomad4 OTH AF: 0.0724

Alfa AF: 0.0723 Hom.: 1261

Bravo AF: 0.0751

TwinsUK AF: 0.0609 AC: 226

ALSPAC AF: 0.0672 AC: 259

ESP6500AA AF: 0.0179 AC: 79

ESP6500EA AF: 0.0699 AC: 601

ExAC AF: 0.0904 AC: 10974

Asia WGS AF: 0.141 AC: 489 AN: 3478

EpiCase AF: 0.0678

EpiControl AF: 0.0639

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

TNFRSF10B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Uncertain	0.99
DEOGEN2	Benign	0.060	T;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	0.0051	T;T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	0.48	N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.52	N;N
REVEL	Benign	0.27
Sift	Benign	0.68	T;T
Sift4G	Benign	1.0	T;T
Polyphen		1.0	D;D
Vest4		0.061
MPC		0.065
ClinPred		0.015	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.083
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs1047266; hg19: chr8-22900701; COSMIC: COSV52391459;