1-12192470-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001066.3(TNFRSF1B):c.497C>G(p.Pro166Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P166L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TNFRSF1B NM_001066.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.41

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1B	NM_001066.3	c.497C>G	p.Pro166Arg	missense_variant	5/10	ENST00000376259.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1B	ENST00000376259.7	c.497C>G	p.Pro166Arg	missense_variant	5/10	1	NM_001066.3	P1
TNFRSF1B	ENST00000492361.1	n.486C>G		non_coding_transcript_exon_variant	4/9	1
TNFRSF1B	ENST00000489921.1	n.209C>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.497C>G (p.P166R) alteration is located in exon 5 (coding exon 5) of the TNFRSF1B gene. This alteration results from a C to G substitution at nucleotide position 497, causing the proline (P) at amino acid position 166 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.031	D
MetaRNN	Uncertain	0.53	D
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.3	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.39	T
PROVEAN	Pathogenic	-4.9	D
REVEL	Benign	0.16
Sift	Benign	0.080	T
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.34		Gain of catalytic residue at P166 (P = 0.0248);
MVP		0.68
MPC		1.1
ClinPred		0.95	D
GERP RS		2.7
Varity_R		0.15
gMVP		0.64

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-12252527;