1-12201968-C-G

Variant names:

• chr1-12201968-C-G
• rs17883432
• NM_001066.3:c.902C>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001066.3(TNFRSF1B):​c.902C>G​(p.Pro301Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000184 in 1,607,616 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00048 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: TNFRSF1B NM_001066.3 missense, splice_region
• Scores: Splicing: ADA: 0.005637
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.14
• Publications: 7 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011523366).

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.902C>G	p.Pro301Arg	missense splice_region	Exon 9 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.902C>G	p.Pro301Arg	missense splice_region	Exon 9 of 10	ENSP00000365435.3
	TNFRSF1B	ENST00000492361.1	TSL:1	n.891C>G		splice_region non_coding_transcript_exon	Exon 8 of 9

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00663

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000300 AC: 71 AN: 236286 AF XY: 0.000270

Gnomad AFR exome AF: 0.000852

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00545

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000285

Gnomad OTH exome AF: 0.000346

GnomAD4 exome AF: 0.000153 AC: 222 AN: 1455302 Hom.: 0 Cov.: 33 AF XY: 0.000149 AC XY: 108 AN XY: 723024

African (AFR) AF: 0.000899 AC: 30 AN: 33382

American (AMR) AF: 0.000113 AC: 5 AN: 44362

Ashkenazi Jewish (ASJ) AF: 0.00500 AC: 130 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39472

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85406

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52318

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5744

European-Non Finnish (NFE) AF: 0.0000235 AC: 26 AN: 1108596

Other (OTH) AF: 0.000483 AC: 29 AN: 60016

GnomAD4 genome AF: 0.000479 AC: 73 AN: 152314 Hom.: 1 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74480

African (AFR) AF: 0.00106 AC: 44 AN: 41576

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00663 AC: 23 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000653 Hom.: 0

Bravo AF: 0.000457

ExAC AF: 0.000281 AC: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Benign	0.97
DEOGEN2	Benign	0.36	T
Eigen	Benign	-0.049
Eigen_PC	Benign	0.037
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.1
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.52
Sift	Benign	0.32	T
Sift4G	Uncertain	0.0040	D
Polyphen		0.25	B
Vest4		0.35
MVP		0.90
MPC		0.49
ClinPred		0.019	T
GERP RS		5.0
Varity_R		0.11
gMVP		0.49
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0056
dbscSNV1_RF	Benign	0.060
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: rs17883432; hg19: chr1-12262025;