rs1061622

Positions:

• chr1-12192898-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 15/20 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
• Clinical Significance: Uncertain significance no assertion criteria provided U:3
• Conservation: PhyloP100: -1.60

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]

ACMG classification

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	Protein	UniProt
TNFRSF1B	NM_001066.3	c.587T>G	p.Met196Arg	missense_variant	6/10	ENST00000376259.7	NP_001057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNFRSF1B	ENST00000376259.7	c.587T>G	p.Met196Arg	missense_variant	6/10	1	NM_001066.3	ENSP00000365435	P1
TNFRSF1B	ENST00000492361.1	n.576T>G		non_coding_transcript_exon_variant	5/9	1
TNFRSF1B	ENST00000489921.1	n.299T>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32885 AN: 151996 Hom.: 3645 Cov.: 32

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

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

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

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

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 provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Aug 07, 2021

Differences in plasma levels of TNFR1 and TNFR2 according to genotypes -

Associated with severe COVID-19 disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Jul 01, 2023

- -

Susceptibility to severe coronavirus disease (COVID-19) Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Feb 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

Other links and lift over

dbSNP: rs1061622; hg19: chr1-12252955; COSMIC: COSV66163731; COSMIC: COSV66163731;