chr1-12192898-T-G

Variant names:

• chr1-12192898-T-G
• rs1061622
• NM_001066.3:c.587T>G

Variant summary

Our verdict is Benign. The variant received -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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• 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
• Publications: 282 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001066.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1B	NM_001066.3	MANE Select	c.587T>G	p.Met196Arg	missense	Exon 6 of 10	NP_001057.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1B	ENST00000376259.7	TSL:1 MANE Select	c.587T>G	p.Met196Arg	missense	Exon 6 of 10	ENSP00000365435.3
	TNFRSF1B	ENST00000492361.1	TSL:1	n.576T>G		non_coding_transcript_exon	Exon 5 of 9
	TNFRSF1B	ENST00000489921.1	TSL:3	n.299T>G		non_coding_transcript_exon	Exon 3 of 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

GnomAD2 exomes AF: 0.216 AC: 54148 AN: 250344 AF XY: 0.221

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 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

African (AFR) AF: 0.210 AC: 7032 AN: 33476

American (AMR) AF: 0.125 AC: 5580 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 7009 AN: 26128

East Asian (EAS) AF: 0.140 AC: 5547 AN: 39688

South Asian (SAS) AF: 0.259 AC: 22327 AN: 86234

European-Finnish (FIN) AF: 0.232 AC: 12362 AN: 53374

Middle Eastern (MID) AF: 0.259 AC: 1493 AN: 5766

European-Non Finnish (NFE) AF: 0.237 AC: 263360 AN: 1111720

Other (OTH) AF: 0.228 AC: 13762 AN: 60376

GnomAD4 genome AF: 0.216 AC: 32928 AN: 152114 Hom.: 3657 Cov.: 32 AF XY: 0.215 AC XY: 15954 AN XY: 74358

African (AFR) AF: 0.204 AC: 8474 AN: 41482

American (AMR) AF: 0.151 AC: 2314 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 914 AN: 3464

East Asian (EAS) AF: 0.153 AC: 791 AN: 5176

South Asian (SAS) AF: 0.255 AC: 1233 AN: 4832

European-Finnish (FIN) AF: 0.232 AC: 2461 AN: 10590

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.236 AC: 16039 AN: 67964

Other (OTH) AF: 0.205 AC: 433 AN: 2110

Alfa AF: 0.228 Hom.: 15243

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

Aug 07, 2021

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Differences in plasma levels of TNFR1 and TNFR2 according to genotypes

Associated with severe COVID-19 disease Uncertain:1

Jul 01, 2023

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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

Feb 09, 2021

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		-1.6
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
Mutation Taster		=73/27	polymorphism (auto)

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

Other links and lift over

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