chr1-12111985-G-A

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

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.280
Variant links:
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]

Genome browser will be placed here

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
TNFRSF8NM_001243.5 linkuse as main transcriptc.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
TNFRSF8ENST00000263932.7 linkuse as main transcriptc.764G>A p.Arg255His missense_variant 7/151 NM_001243.5 ENSP00000263932 P1P28908-1
TNFRSF8ENST00000417814.3 linkuse as main transcriptc.431G>A p.Arg144His missense_variant 6/141 ENSP00000390650 P28908-3
TNFRSF8ENST00000514649.5 linkuse as main transcriptc.*508G>A 3_prime_UTR_variant, NMD_transcript_variant 6/141 ENSP00000421938

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251040
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135786
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000981
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000123
AC:
18
AN:
1461660
Hom.:
0
Cov.:
31
AF XY:
0.0000138
AC XY:
10
AN XY:
727120
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000812
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.00000630
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152230
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000412
AC:
5
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

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 submitterclinical testingAmbry GeneticsAug 13, 2021The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
20
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.21
.;T
Eigen
Benign
0.029
Eigen_PC
Benign
-0.11
FATHMM_MKL
Benign
0.26
N
LIST_S2
Benign
0.82
T;T
M_CAP
Benign
0.0035
T
MetaRNN
Uncertain
0.44
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
.;L
MutationTaster
Benign
0.99
N;N
PrimateAI
Benign
0.24
T
PROVEAN
Uncertain
-2.5
D;N
REVEL
Benign
0.15
Sift
Benign
0.044
D;D
Sift4G
Uncertain
0.056
T;T
Polyphen
0.89
.;P
Vest4
0.21
MutPred
0.57
.;Gain of catalytic residue at R255 (P = 0.0755);
MVP
0.34
MPC
0.28
ClinPred
0.59
D
GERP RS
0.027
Varity_R
0.032
gMVP
0.67

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754880340; hg19: chr1-12172042; API