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GeneBe

rs1061622

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001066.3(TNFRSF1B):c.587T>G(p.Met196Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.23 in 1,613,590 control chromosomes in the GnomAD database, including 43,833 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.22 ( 3657 hom., cov: 32)
Exomes 𝑓: 0.23 ( 40176 hom. )

Consequence

TNFRSF1B
NM_001066.3 missense

Scores

18

Clinical Significance

Uncertain significance no assertion criteria provided U:3

Conservation

PhyloP100: -1.60
Variant links:
Genes affected
TNFRSF1B (HGNC:11917): (TNF receptor superfamily member 1B) The protein encoded by this gene is a member of the TNF-receptor superfamily. This protein and TNF-receptor 1 form a heterocomplex that mediates the recruitment of two anti-apoptotic proteins, c-IAP1 and c-IAP2, which possess E3 ubiquitin ligase activity. The function of IAPs in TNF-receptor signalling is unknown, however, c-IAP1 is thought to potentiate TNF-induced apoptosis by the ubiquitination and degradation of TNF-receptor-associated factor 2, which mediates anti-apoptotic signals. Knockout studies in mice also suggest a role of this protein in protecting neurons from apoptosis by stimulating antioxidative pathways. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0025791824).
BA1
GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.243 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TNFRSF1BNM_001066.3 linkuse as main transcriptc.587T>G p.Met196Arg missense_variant 6/10 ENST00000376259.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNFRSF1BENST00000376259.7 linkuse as main transcriptc.587T>G p.Met196Arg missense_variant 6/101 NM_001066.3 P1P20333-1
TNFRSF1BENST00000492361.1 linkuse as main transcriptn.576T>G non_coding_transcript_exon_variant 5/91
TNFRSF1BENST00000489921.1 linkuse as main transcriptn.299T>G non_coding_transcript_exon_variant 3/33

Frequencies

GnomAD3 genomes
AF:
0.216
AC:
32885
AN:
151996
Hom.:
3645
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.204
Gnomad AMI
AF:
0.212
Gnomad AMR
AF:
0.152
Gnomad ASJ
AF:
0.264
Gnomad EAS
AF:
0.152
Gnomad SAS
AF:
0.255
Gnomad FIN
AF:
0.232
Gnomad MID
AF:
0.278
Gnomad NFE
AF:
0.236
Gnomad OTH
AF:
0.207
GnomAD3 exomes
AF:
0.216
AC:
54148
AN:
250344
Hom.:
6096
AF XY:
0.221
AC XY:
29964
AN XY:
135350
show subpopulations
Gnomad AFR exome
AF:
0.208
Gnomad AMR exome
AF:
0.120
Gnomad ASJ exome
AF:
0.269
Gnomad EAS exome
AF:
0.156
Gnomad SAS exome
AF:
0.262
Gnomad FIN exome
AF:
0.225
Gnomad NFE exome
AF:
0.238
Gnomad OTH exome
AF:
0.224
GnomAD4 exome
AF:
0.232
AC:
338472
AN:
1461476
Hom.:
40176
Cov.:
37
AF XY:
0.233
AC XY:
169357
AN XY:
727046
show subpopulations
Gnomad4 AFR exome
AF:
0.210
Gnomad4 AMR exome
AF:
0.125
Gnomad4 ASJ exome
AF:
0.268
Gnomad4 EAS exome
AF:
0.140
Gnomad4 SAS exome
AF:
0.259
Gnomad4 FIN exome
AF:
0.232
Gnomad4 NFE exome
AF:
0.237
Gnomad4 OTH exome
AF:
0.228
GnomAD4 genome
AF:
0.216
AC:
32928
AN:
152114
Hom.:
3657
Cov.:
32
AF XY:
0.215
AC XY:
15954
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.204
Gnomad4 AMR
AF:
0.151
Gnomad4 ASJ
AF:
0.264
Gnomad4 EAS
AF:
0.153
Gnomad4 SAS
AF:
0.255
Gnomad4 FIN
AF:
0.232
Gnomad4 NFE
AF:
0.236
Gnomad4 OTH
AF:
0.205
Alfa
AF:
0.231
Hom.:
6914
Bravo
AF:
0.208
TwinsUK
AF:
0.241
AC:
894
ALSPAC
AF:
0.239
AC:
922
ESP6500AA
AF:
0.211
AC:
929
ESP6500EA
AF:
0.241
AC:
2069
ExAC
AF:
0.224
AC:
27145
Asia WGS
AF:
0.178
AC:
624
AN:
3478
EpiCase
AF:
0.233
EpiControl
AF:
0.234

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Susceptibility to severe coronavirus disease (COVID-19) due to high plasma levels of TNF, TNFR, and/or TNFR2 Uncertain:1
Uncertain significance, no assertion criteria providedresearchHLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio VillegasAug 07, 2021Differences in plasma levels of TNFR1 and TNFR2 according to genotypes -
Associated with severe COVID-19 disease Uncertain:1
Uncertain significance, no assertion criteria providedresearchHLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio VillegasJul 01, 2023- -
Susceptibility to severe coronavirus disease (COVID-19) Uncertain:1
Uncertain significance, no assertion criteria providedresearchHLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio VillegasFeb 09, 2021- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Benign
-0.72
T
BayesDel_noAF
Benign
-0.66
Cadd
Benign
2.5
Dann
Benign
0.84
DEOGEN2
Benign
0.12
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.038
N
LIST_S2
Benign
0.56
T
MetaRNN
Benign
0.0026
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.30
N
MutationTaster
Benign
1.0
P
PrimateAI
Benign
0.25
T
PROVEAN
Benign
-0.40
N
REVEL
Benign
0.044
Sift
Benign
0.26
T
Sift4G
Benign
0.29
T
Polyphen
0.0
B
Vest4
0.059
MPC
0.53
ClinPred
0.000027
T
GERP RS
-4.1
Varity_R
0.27
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs1061622; hg19: chr1-12252955; COSMIC: COSV66163731; COSMIC: COSV66163731; API