8-23201811-C-G

Variant names:

• chr8-23201811-C-G
• rs20575
• NM_003844.4:c.626G>C

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 91 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003844.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF10A	NM_003844.4	MANE Select	c.626G>C	p.Arg209Thr	missense	Exon 4 of 10	NP_003835.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF10A	ENST00000221132.8	TSL:1 MANE Select	c.626G>C	p.Arg209Thr	missense	Exon 4 of 10	ENSP00000221132.3	O00220
	TNFRSF10A	ENST00000613472.1	TSL:1	c.152G>C	p.Arg51Thr	missense	Exon 3 of 9	ENSP00000480778.1	F8U8C0
	TNFRSF10A	ENST00000901503.1		c.626G>C	p.Arg209Thr	missense	Exon 4 of 9	ENSP00000571562.1

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

GnomAD2 exomes AF: 0.537 AC: 134746 AN: 250946 AF XY: 0.538

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 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

African (AFR) AF: 0.305 AC: 10211 AN: 33470

American (AMR) AF: 0.647 AC: 28911 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 13192 AN: 26126

East Asian (EAS) AF: 0.982 AC: 38987 AN: 39694

South Asian (SAS) AF: 0.650 AC: 56043 AN: 86220

European-Finnish (FIN) AF: 0.415 AC: 22139 AN: 53372

Middle Eastern (MID) AF: 0.497 AC: 2863 AN: 5766

European-Non Finnish (NFE) AF: 0.467 AC: 518847 AN: 1110890

Other (OTH) AF: 0.506 AC: 30499 AN: 60334

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

African (AFR) AF: 0.317 AC: 13026 AN: 41122

American (AMR) AF: 0.579 AC: 8846 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.494 AC: 1715 AN: 3472

East Asian (EAS) AF: 0.976 AC: 5065 AN: 5190

South Asian (SAS) AF: 0.667 AC: 3213 AN: 4816

European-Finnish (FIN) AF: 0.405 AC: 4283 AN: 10570

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.462 AC: 31392 AN: 67960

Other (OTH) AF: 0.488 AC: 1028 AN: 2106

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 v4.9

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
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.00019	N
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000010	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-0.41
PrimateAI	Benign	0.28	T
PROVEAN	Benign	4.3	N
REVEL	Benign	0.078
Sift	Benign	1.0	T
Sift4G	Benign	1.0	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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