rs1047266

Positions:

• chr8-23043188-G-A
• chr8-23043188-G-C
• chr8-23043188-G-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 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 (no stars). 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 no assertion criteria provided 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 -13 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 no_assertion_criteria_provided, 0 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	Protein	UniProt
TNFRSF10B	NM_003842.5	c.200C>T	p.Ala67Val	missense_variant	2/9	ENST00000276431.9	NP_003833.4
TNFRSF10B	NM_147187.3	c.200C>T	p.Ala67Val	missense_variant	2/10		NP_671716.2
TNFRSF10B	NR_027140.2	n.282-12316C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF10B	ENST00000276431.9	c.200C>T	p.Ala67Val	missense_variant	2/9	1	NM_003842.5	ENSP00000276431	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: no assertion criteria provided

Submissions by phenotype

TNFRSF10B-related disorder Benign:1

Benign, no assertion criteria provided

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;