1-12115663-A-G

Position:

• chr1-12115663-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001243.5(TNFRSF8):​c.880A>G​(p.Thr294Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TNFRSF8 NM_001243.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.459

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047857314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNFRSF8	NM_001243.5	c.880A>G	p.Thr294Ala	missense_variant	8/15	ENST00000263932.7	NP_001234.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF8	ENST00000263932.7	c.880A>G	p.Thr294Ala	missense_variant	8/15	1	NM_001243.5	ENSP00000263932	P1
TNFRSF8	ENST00000417814.3	c.547A>G	p.Thr183Ala	missense_variant	7/14	1		ENSP00000390650
TNFRSF8	ENST00000514649.5	c.*624A>G		3_prime_UTR_variant, NMD_transcript_variant	7/14	1		ENSP00000421938

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 24, 2023

The c.880A>G (p.T294A) alteration is located in exon 8 (coding exon 8) of the TNFRSF8 gene. This alteration results from a A to G substitution at nucleotide position 880, causing the threonine (T) at amino acid position 294 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.0
DANN	Benign	0.96
DEOGEN2	Benign	0.21	.;T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.10	T;T
M_CAP	Benign	0.0019	T
MetaRNN	Benign	0.048	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.3	.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.073
Sift	Benign	0.28	T;T
Sift4G	Benign	0.33	T;T
Polyphen		0.11	.;B
Vest4		0.10
MutPred		0.18		.;Loss of glycosylation at T294 (P = 0.1737);
MVP		0.082
MPC		0.20
ClinPred		0.077	T
GERP RS		1.6
Varity_R		0.017
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-12175720;