8-23201811-C-G

Position:

• chr8-23201811-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003844.4(TNFRSF10A):​c.626G>C​(p.Arg209Thr) 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 1,612,304 control chromosomes in the GnomAD database, including 204,041 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 same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.46 (17292 hom., cov: 32)
  • Exomes 𝑓: 0.49 (186749 hom.)
• Consequence: TNFRSF10A NM_003844.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.414

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.0118974E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.953 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF10A	NM_003844.4	c.626G>C	p.Arg209Thr	missense_variant	4/10	ENST00000221132.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF10A	ENST00000221132.8	c.626G>C	p.Arg209Thr	missense_variant	4/10	1	NM_003844.4	P1
TNFRSF10A	ENST00000613472.1	c.152G>C	p.Arg51Thr	missense_variant	3/9	1
TNFRSF10A	ENST00000524158.5	c.20G>C	p.Arg7Thr	missense_variant	4/7	5

Frequencies

GnomAD3 genomes AF: 0.456 AC: 69062 AN: 151616 Hom.: 17277 Cov.: 32

Gnomad AFR AF: 0.317

Gnomad AMI AF: 0.462

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.494

Gnomad EAS AF: 0.976

Gnomad SAS AF: 0.668

Gnomad FIN AF: 0.405

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.462

Gnomad OTH AF: 0.485

GnomAD3 exomes AF: 0.537 AC: 134746 AN: 250946 Hom.: 39513 AF XY: 0.538 AC XY: 72944 AN XY: 135632

Gnomad AFR exome AF: 0.312

Gnomad AMR exome AF: 0.659

Gnomad ASJ exome AF: 0.507

Gnomad EAS exome AF: 0.976

Gnomad SAS exome AF: 0.652

Gnomad FIN exome AF: 0.410

Gnomad NFE exome AF: 0.458

Gnomad OTH exome AF: 0.506

GnomAD4 exome AF: 0.494 AC: 721692 AN: 1460580 Hom.: 186749 Cov.: 38 AF XY: 0.499 AC XY: 362274 AN XY: 726638

Gnomad4 AFR exome AF: 0.305

Gnomad4 AMR exome AF: 0.647

Gnomad4 ASJ exome AF: 0.505

Gnomad4 EAS exome AF: 0.982

Gnomad4 SAS exome AF: 0.650

Gnomad4 FIN exome AF: 0.415

Gnomad4 NFE exome AF: 0.467

Gnomad4 OTH exome AF: 0.506

GnomAD4 genome AF: 0.456 AC: 69114 AN: 151724 Hom.: 17292 Cov.: 32 AF XY: 0.462 AC XY: 34249 AN XY: 74172

Gnomad4 AFR AF: 0.317

Gnomad4 AMR AF: 0.579

Gnomad4 ASJ AF: 0.494

Gnomad4 EAS AF: 0.976

Gnomad4 SAS AF: 0.667

Gnomad4 FIN AF: 0.405

Gnomad4 NFE AF: 0.462

Gnomad4 OTH AF: 0.488

Alfa AF: 0.476 Hom.: 13399

Bravo AF: 0.461

TwinsUK AF: 0.462 AC: 1714

ALSPAC AF: 0.486 AC: 1872

ESP6500AA AF: 0.316 AC: 1393

ESP6500EA AF: 0.459 AC: 3944

ExAC AF: 0.527 AC: 63953

Asia WGS AF: 0.741 AC: 2575 AN: 3478

EpiCase AF: 0.460

EpiControl AF: 0.451

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	0.11
DANN	Benign	0.098
DEOGEN2	Benign	0.088	T;T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00019	N
LIST_S2	Benign	0.15	T;T;T
MetaRNN	Benign	0.0000010	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.1	N;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.28	T
PROVEAN	Benign	4.3	N;.;N
REVEL	Benign	0.078
Sift	Benign	1.0	T;.;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0	B;.;.
Vest4		0.050
MPC		0.093
ClinPred		0.0019	T
GERP RS		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.044
gMVP		0.54

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: rs20575; hg19: chr8-23059324; COSMIC: COSV55325410; COSMIC: COSV55325410;