rs3397

Variant names:

• chr1-12207235-C-T
• rs3397
• NM_001066.3:c.*215C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001066.3(TNFRSF1B):​c.*215C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.57 in 473,266 control chromosomes in the GnomAD database, including 81,831 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.51 (22516 hom., cov: 33)
  • Exomes 𝑓: 0.60 (59315 hom.)
• Consequence: TNFRSF1B NM_001066.3 3_prime_UTR
• Clinical Significance: Uncertain significance no assertion criteria provided U:3
• Conservation: PhyloP100: -0.400
• Publications: 82 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 (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.663 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1B	NM_001066.3	MANE Select	c.*215C>T		3_prime_UTR	Exon 10 of 10	NP_001057.1	P20333-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF1B	ENST00000376259.7	TSL:1 MANE Select	c.*215C>T		3_prime_UTR	Exon 10 of 10	ENSP00000365435.3	P20333-1
	TNFRSF1B	ENST00000492361.1	TSL:1	n.1590C>T		non_coding_transcript_exon	Exon 9 of 9
	TNFRSF1B	ENST00000941756.1		c.*215C>T		3_prime_UTR	Exon 10 of 10	ENSP00000611815.1

Frequencies

GnomAD3 genomes AF: 0.510 AC: 77531 AN: 152072 Hom.: 22512 Cov.: 33

Gnomad AFR AF: 0.226

Gnomad AMI AF: 0.498

Gnomad AMR AF: 0.673

Gnomad ASJ AF: 0.667

Gnomad EAS AF: 0.305

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.623

Gnomad MID AF: 0.668

Gnomad NFE AF: 0.640

Gnomad OTH AF: 0.535

GnomAD4 exome AF: 0.599 AC: 192198 AN: 321076 Hom.: 59315 Cov.: 5 AF XY: 0.600 AC XY: 98421 AN XY: 163988

African (AFR) AF: 0.239 AC: 2140 AN: 8956

American (AMR) AF: 0.703 AC: 7689 AN: 10936

Ashkenazi Jewish (ASJ) AF: 0.670 AC: 7047 AN: 10514

East Asian (EAS) AF: 0.343 AC: 8484 AN: 24714

South Asian (SAS) AF: 0.478 AC: 5996 AN: 12538

European-Finnish (FIN) AF: 0.608 AC: 14145 AN: 23268

Middle Eastern (MID) AF: 0.661 AC: 1044 AN: 1580

European-Non Finnish (NFE) AF: 0.643 AC: 134175 AN: 208646

Other (OTH) AF: 0.576 AC: 11478 AN: 19924

GnomAD4 genome AF: 0.510 AC: 77556 AN: 152190 Hom.: 22516 Cov.: 33 AF XY: 0.511 AC XY: 38008 AN XY: 74394

African (AFR) AF: 0.226 AC: 9387 AN: 41536

American (AMR) AF: 0.673 AC: 10300 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.667 AC: 2316 AN: 3470

East Asian (EAS) AF: 0.306 AC: 1583 AN: 5178

South Asian (SAS) AF: 0.432 AC: 2083 AN: 4822

European-Finnish (FIN) AF: 0.623 AC: 6595 AN: 10590

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.640 AC: 43522 AN: 67984

Other (OTH) AF: 0.531 AC: 1121 AN: 2110

Alfa AF: 0.576 Hom.: 9470

Bravo AF: 0.506

Asia WGS AF: 0.340 AC: 1183 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Associated with severe COVID-19 disease (1)
-	1	-	Susceptibility to severe coronavirus disease (COVID-19) (1)
-	1	-	Susceptibility to severe coronavirus disease (COVID-19) due to high plasma levels of TNF, TNFR, and/or TNFR3 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.5
DANN	Benign	0.86
PhyloP100		-0.40
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3397; hg19: chr1-12267292; COSMIC: COSV66164003;