NM_001066.3:c.165C>G

Variant names:

• chr1-12188882-C-G
• rs1372059294
• NM_001066.3:c.165C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001066.3(TNFRSF1B):​c.165C>G​(p.Ser55Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S55N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TNFRSF1B NM_001066.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.599
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21403354).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3	c.165C>G	p.Ser55Arg	missense_variant	Exon 2 of 10	ENST00000376259.7	NP_001057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1B	ENST00000376259.7	c.165C>G	p.Ser55Arg	missense_variant	Exon 2 of 10	1	NM_001066.3	ENSP00000365435.3
TNFRSF1B	ENST00000536782.2	c.165C>G	p.Ser55Arg	missense_variant	Exon 2 of 5	1		ENSP00000440425.1
TNFRSF1B	ENST00000492361.1	n.168-2075C>G		intron_variant	Intron 1 of 8	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.027	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	13
DANN	Benign	0.72
DEOGEN2	Uncertain	0.52	.;D
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.64	T;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.45	T
MutationAssessor	Benign	1.7	.;L
PhyloP100		0.60
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-2.3	N;N
REVEL	Benign	0.23
Sift	Benign	0.075	T;D
Sift4G	Benign	0.069	T;D
Polyphen		0.26	.;B
Vest4		0.30
MutPred		0.53		Loss of ubiquitination at K56 (P = 0.0496);Loss of ubiquitination at K56 (P = 0.0496);
MVP		0.52
MPC		0.59
ClinPred		0.13	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.71
Mutation Taster		=74/26	polymorphism

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: rs1372059294; hg19: chr1-12248939;