1-12111992-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001243.5(TNFRSF8):c.771G>A(p.Thr257=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00363 in 1,614,148 control chromosomes in the GnomAD database, including 159 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (87 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (72 hom.)
• Consequence: TNFRSF8 NM_001243.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.19

Genes affected

TNFRSF8 (HGNC:11923): (TNF receptor superfamily member 8) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor is expressed by activated, but not by resting, T and B cells. TRAF2 and TRAF5 can interact with this receptor, and mediate the signal transduction that leads to the activation of NF-kappaB. This receptor is a positive regulator of apoptosis, and also has been shown to limit the proliferative potential of autoreactive CD8 effector T cells and protect the body against autoimmunity. Two alternatively spliced transcript variants of this gene encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 1-12111992-G-A is Benign according to our data. Variant chr1-12111992-G-A is described in ClinVar as [Benign]. Clinvar id is 775513.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-1.19 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF8	NM_001243.5	c.771G>A	p.Thr257=	synonymous_variant	7/15	ENST00000263932.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF8	ENST00000263932.7	c.771G>A	p.Thr257=	synonymous_variant	7/15	1	NM_001243.5	P1
TNFRSF8	ENST00000417814.3	c.438G>A	p.Thr146=	synonymous_variant	6/14	1
TNFRSF8	ENST00000514649.5	c.*515G>A		3_prime_UTR_variant, NMD_transcript_variant	6/14	1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2711 AN: 152230 Hom.: 87 Cov.: 32

Gnomad AFR AF: 0.0618

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000426

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00516 AC: 1295 AN: 250964 Hom.: 30 AF XY: 0.00376 AC XY: 510 AN XY: 135756

Gnomad AFR exome AF: 0.0639

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000591

Gnomad OTH exome AF: 0.00245

GnomAD4 exome AF: 0.00215 AC: 3141 AN: 1461800 Hom.: 72 Cov.: 31 AF XY: 0.00185 AC XY: 1342 AN XY: 727196

Gnomad4 AFR exome AF: 0.0650

Gnomad4 AMR exome AF: 0.00474

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000197

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000288

Gnomad4 OTH exome AF: 0.00548

GnomAD4 genome AF: 0.0179 AC: 2723 AN: 152348 Hom.: 87 Cov.: 32 AF XY: 0.0171 AC XY: 1272 AN XY: 74506

Gnomad4 AFR AF: 0.0619

Gnomad4 AMR AF: 0.00588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.0111 Hom.: 16

Bravo AF: 0.0199

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000327

EpiControl AF: 0.000889

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 03, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
Cadd	Benign	6.0
Dann	Benign	0.71

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: rs2230623; hg19: chr1-12172049;