rs20577

Positions:

• chr8-23224964-G-A

Variant summary

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

The NM_003844.4(TNFRSF10A):​c.98C>T​(p.Thr33Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,600,150 control chromosomes in the GnomAD database, including 2,537 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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 0.072 (1345 hom., cov: 30)
  • Exomes 𝑓: 0.0072 (1192 hom.)
• Consequence: TNFRSF10A NM_003844.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.531

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]

TNFRSF10A-DT (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0050595105).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF10A	NM_003844.4	c.98C>T	p.Thr33Ile	missense_variant	1/10	ENST00000221132.8	NP_003835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF10A	ENST00000221132.8	c.98C>T	p.Thr33Ile	missense_variant	1/10	1	NM_003844.4	ENSP00000221132.3
TNFRSF10A	ENST00000613472.1	c.31+67C>T		intron_variant		1		ENSP00000480778.1
TNFRSF10A-DT	ENST00000517774.1	n.421+73G>A		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.0714 AC: 10858 AN: 152084 Hom.: 1339 Cov.: 30

Gnomad AFR AF: 0.250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0235

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000735

Gnomad OTH AF: 0.0450

GnomAD3 exomes AF: 0.0178 AC: 3959 AN: 222964 Hom.: 474 AF XY: 0.0132 AC XY: 1603 AN XY: 121680

Gnomad AFR exome AF: 0.262

Gnomad AMR exome AF: 0.0105

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000249

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000671

Gnomad OTH exome AF: 0.0103

GnomAD4 exome AF: 0.00719 AC: 10405 AN: 1447948 Hom.: 1192 Cov.: 31 AF XY: 0.00614 AC XY: 4416 AN XY: 719212

Gnomad4 AFR exome AF: 0.257

Gnomad4 AMR exome AF: 0.0123

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000261

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000321

Gnomad4 OTH exome AF: 0.0150

GnomAD4 genome AF: 0.0715 AC: 10887 AN: 152202 Hom.: 1345 Cov.: 30 AF XY: 0.0686 AC XY: 5108 AN XY: 74426

Gnomad4 AFR AF: 0.250

Gnomad4 AMR AF: 0.0234

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000735

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.0243 Hom.: 319

Bravo AF: 0.0816

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.222 AC: 977

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.0218 AC: 2634

Asia WGS AF: 0.0140 AC: 51 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.4
DANN	Benign	0.90
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.012	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.24
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.042
MPC		0.077
ClinPred		0.012	T
GERP RS		0.69
Varity_R		0.11
gMVP		0.23

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: rs20577; hg19: chr8-23082477; COSMIC: COSV55326212; COSMIC: COSV55326212;