rs20576

Positions:

• chr8-23200707-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000221132.8(TNFRSF10A):​c.683A>C​(p.Glu228Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.181 in 1,605,418 control chromosomes in the GnomAD database, including 28,771 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.14 (1965 hom., cov: 31)
  • Exomes 𝑓: 0.19 (26806 hom.)
• Consequence: TNFRSF10A ENST00000221132.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.03

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010643601).
• BP6: Variant 8-23200707-T-G is Benign according to our data. Variant chr8-23200707-T-G is described in ClinVar as [Benign]. Clinvar id is 1253334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.199 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF10A	NM_003844.4	c.683A>C	p.Glu228Ala	missense_variant	5/10	ENST00000221132.8	NP_003835.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF10A	ENST00000221132.8	c.683A>C	p.Glu228Ala	missense_variant	5/10	1	NM_003844.4	ENSP00000221132	P1
TNFRSF10A	ENST00000613472.1	c.209A>C	p.Glu70Ala	missense_variant	4/9	1		ENSP00000480778
TNFRSF10A	ENST00000524158.5	c.77A>C	p.Glu26Ala	missense_variant	5/7	5		ENSP00000428884

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21716 AN: 151290 Hom.: 1965 Cov.: 31

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.246

Gnomad AMR AF: 0.143

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0927

Gnomad FIN AF: 0.231

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.202

Gnomad OTH AF: 0.162

GnomAD3 exomes AF: 0.151 AC: 38009 AN: 251454 Hom.: 3544 AF XY: 0.155 AC XY: 21075 AN XY: 135904

Gnomad AFR exome AF: 0.0317

Gnomad AMR exome AF: 0.106

Gnomad ASJ exome AF: 0.198

Gnomad EAS exome AF: 0.0159

Gnomad SAS exome AF: 0.0885

Gnomad FIN exome AF: 0.215

Gnomad NFE exome AF: 0.203

Gnomad OTH exome AF: 0.178

GnomAD4 exome AF: 0.185 AC: 269208 AN: 1454004 Hom.: 26806 Cov.: 53 AF XY: 0.183 AC XY: 132429 AN XY: 723542

Gnomad4 AFR exome AF: 0.0320

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.199

Gnomad4 EAS exome AF: 0.0148

Gnomad4 SAS exome AF: 0.0925

Gnomad4 FIN exome AF: 0.216

Gnomad4 NFE exome AF: 0.205

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.143 AC: 21712 AN: 151414 Hom.: 1965 Cov.: 31 AF XY: 0.144 AC XY: 10647 AN XY: 73964

Gnomad4 AFR AF: 0.0377

Gnomad4 AMR AF: 0.143

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.0161

Gnomad4 SAS AF: 0.0933

Gnomad4 FIN AF: 0.231

Gnomad4 NFE AF: 0.202

Gnomad4 OTH AF: 0.160

Alfa AF: 0.190 Hom.: 6465

Bravo AF: 0.134

TwinsUK AF: 0.206 AC: 764

ALSPAC AF: 0.195 AC: 753

ESP6500AA AF: 0.0470 AC: 207

ESP6500EA AF: 0.200 AC: 1720

ExAC AF: 0.149 AC: 18104

Asia WGS AF: 0.0600 AC: 208 AN: 3478

EpiCase AF: 0.210

EpiControl AF: 0.217

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 18, 2020	This variant is associated with the following publications: (PMID: 21484799, 23658636, 22401174) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	12
DANN	Benign	0.93
DEOGEN2	Uncertain	0.57	D;D;D
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.51	T;T;T
MetaRNN	Benign	0.011	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;.;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-2.3	N;.;D
REVEL	Benign	0.11
Sift	Benign	0.037	D;.;D
Sift4G	Uncertain	0.053	T;D;T
Polyphen		0.31	B;.;.
Vest4		0.13
MPC		0.12
ClinPred		0.0099	T
GERP RS		0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs20576; hg19: chr8-23058220; COSMIC: COSV55325303; COSMIC: COSV55325303;