chr8-23028507-A-G

Position:

• chr8-23028507-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003842.5(TNFRSF10B):​c.572T>C​(p.Val191Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.891 in 1,614,022 control chromosomes in the GnomAD database, including 641,531 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.86 (56444 hom., cov: 32)
  • Exomes 𝑓: 0.89 (585087 hom.)
• Consequence: TNFRSF10B NM_003842.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.0780

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=6.5096305E-7).
• BP6: Variant 8-23028507-A-G is Benign according to our data. Variant chr8-23028507-A-G is described in ClinVar as [Benign]. Clinvar id is 3059674.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr8-23028507-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.958 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF10B	NM_003842.5	c.572T>C	p.Val191Ala	missense_variant	5/9	ENST00000276431.9
TNFRSF10B	NM_147187.3	c.550+22T>C		intron_variant
TNFRSF10B	NR_027140.2	n.581+22T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF10B	ENST00000276431.9	c.572T>C	p.Val191Ala	missense_variant	5/9	1	NM_003842.5	P2

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130477 AN: 152032 Hom.: 56410 Cov.: 32

Gnomad AFR AF: 0.749

Gnomad AMI AF: 0.914

Gnomad AMR AF: 0.872

Gnomad ASJ AF: 0.906

Gnomad EAS AF: 0.981

Gnomad SAS AF: 0.863

Gnomad FIN AF: 0.936

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.897

Gnomad OTH AF: 0.856

GnomAD3 exomes AF: 0.892 AC: 224343 AN: 251476 Hom.: 100438 AF XY: 0.894 AC XY: 121443 AN XY: 135908

Gnomad AFR exome AF: 0.749

Gnomad AMR exome AF: 0.885

Gnomad ASJ exome AF: 0.910

Gnomad EAS exome AF: 0.980

Gnomad SAS exome AF: 0.867

Gnomad FIN exome AF: 0.933

Gnomad NFE exome AF: 0.898

Gnomad OTH exome AF: 0.888

GnomAD4 exome AF: 0.894 AC: 1306908 AN: 1461872 Hom.: 585087 Cov.: 76 AF XY: 0.894 AC XY: 650060 AN XY: 727244

Gnomad4 AFR exome AF: 0.739

Gnomad4 AMR exome AF: 0.883

Gnomad4 ASJ exome AF: 0.913

Gnomad4 EAS exome AF: 0.975

Gnomad4 SAS exome AF: 0.866

Gnomad4 FIN exome AF: 0.933

Gnomad4 NFE exome AF: 0.896

Gnomad4 OTH exome AF: 0.887

GnomAD4 genome AF: 0.858 AC: 130575 AN: 152150 Hom.: 56444 Cov.: 32 AF XY: 0.862 AC XY: 64084 AN XY: 74374

Gnomad4 AFR AF: 0.749

Gnomad4 AMR AF: 0.872

Gnomad4 ASJ AF: 0.906

Gnomad4 EAS AF: 0.981

Gnomad4 SAS AF: 0.864

Gnomad4 FIN AF: 0.936

Gnomad4 NFE AF: 0.897

Gnomad4 OTH AF: 0.857

Alfa AF: 0.892 Hom.: 61935

Bravo AF: 0.849

TwinsUK AF: 0.900 AC: 3339

ALSPAC AF: 0.889 AC: 3428

ESP6500AA AF: 0.760 AC: 3348

ESP6500EA AF: 0.902 AC: 7754

ExAC AF: 0.890 AC: 108043

Asia WGS AF: 0.916 AC: 3184 AN: 3478

EpiCase AF: 0.892

EpiControl AF: 0.893

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

Sep 24, 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	0.071
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.15
DANN	Benign	0.20
DEOGEN2	Benign	0.027	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0013	N
LIST_S2	Benign	0.14	T
MetaRNN	Benign	6.5e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.49	N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.17
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.0020
MPC		0.070
ClinPred		0.00031	T
GERP RS		0.015
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		3.1
Varity_R		0.011
gMVP		0.40

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

Other links and lift over

dbSNP: rs13265018; hg19: chr8-22886020;