Genetic Variant TNFRSF1B:p.Thr70Pro (chr1-12190986-A-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001066.3(TNFRSF1B):c.208A>C(p.Thr70Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TNFRSF1B
NM_001066.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.70

Publications

0 publications found

Variant links:

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]

TNFRSF1B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3901491).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3 link	c.208A>C	p.Thr70Pro	missense_variant	Exon 3 of 10	ENST00000376259.7	NP_001057.1	P20333-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFRSF1B	ENST00000376259.7 link	c.208A>C	p.Thr70Pro	missense_variant	Exon 3 of 10	1	NM_001066.3	ENSP00000365435.3	P20333-1
TNFRSF1B	ENST00000536782.2 link	c.208A>C	p.Thr70Pro	missense_variant	Exon 3 of 5	1		ENSP00000440425.1	B5A977
TNFRSF1B	ENST00000492361.1 link	n.197A>C		non_coding_transcript_exon_variant	Exon 2 of 9	1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000342

AC:

AN:

1461844

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111986

Other (OTH)

AF:

0.00

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 11, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.208A>C (p.T70P) alteration is located in exon 3 (coding exon 3) of the TNFRSF1B gene. This alteration results from a A to C substitution at nucleotide position 208, causing the threonine (T) at amino acid position 70 to be replaced by a proline (P). 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

Uncertain

0.40

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.70

.;D

Eigen

Benign

0.049

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.67

T;T

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.39

T;T

MetaSVM

Uncertain

0.058

MutationAssessor

Uncertain

2.5

.;M

PhyloP100

2.7

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-3.6

D;D

REVEL

Uncertain

0.49

Sift

Uncertain

0.014

D;D

Sift4G

Uncertain

0.016

D;D

Polyphen

0.92

.;P

Vest4

0.33

MutPred

0.59

Gain of disorder (P = 0.1054);Gain of disorder (P = 0.1054);

MVP

0.86

MPC

1.2

ClinPred

0.87

GERP RS

2.9

Varity_R

0.53

gMVP

0.80

Mutation Taster

=72/28

polymorphism

(source)

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

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1-12190986-A-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over