chr1-12111985-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_001243.5(TNFRSF8):c.764G>A(p.Arg255His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
TNFRSF8
NM_001243.5 missense
NM_001243.5 missense
Scores
1
3
15
Clinical Significance
Conservation
PhyloP100: 0.280
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TNFRSF8 | NM_001243.5 | c.764G>A | p.Arg255His | missense_variant | 7/15 | ENST00000263932.7 | NP_001234.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TNFRSF8 | ENST00000263932.7 | c.764G>A | p.Arg255His | missense_variant | 7/15 | 1 | NM_001243.5 | ENSP00000263932 | P1 | |
TNFRSF8 | ENST00000417814.3 | c.431G>A | p.Arg144His | missense_variant | 6/14 | 1 | ENSP00000390650 | |||
TNFRSF8 | ENST00000514649.5 | c.*508G>A | 3_prime_UTR_variant, NMD_transcript_variant | 6/14 | 1 | ENSP00000421938 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251040Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135786
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GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461660Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10AN XY: 727120
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152230Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74362
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Aug 13, 2021 | The c.764G>A (p.R255H) alteration is located in exon 7 (coding exon 7) of the TNFRSF8 gene. This alteration results from a G to A substitution at nucleotide position 764, causing the arginine (R) at amino acid position 255 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Pathogenic
DEOGEN2
Benign
.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T
M_CAP
Benign
T
MetaRNN
Uncertain
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
.;L
MutationTaster
Benign
N;N
PrimateAI
Benign
T
PROVEAN
Uncertain
D;N
REVEL
Benign
Sift
Benign
D;D
Sift4G
Uncertain
T;T
Polyphen
0.89
.;P
Vest4
MutPred
0.57
.;Gain of catalytic residue at R255 (P = 0.0755);
MVP
MPC
0.28
ClinPred
D
GERP RS
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at