chr1-12192865-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001066.3(TNFRSF1B):ā€‹c.554G>Cā€‹(p.Cys185Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000342 in 1,460,780 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 0.0000034 ( 0 hom. )

Consequence

TNFRSF1B
NM_001066.3 missense, splice_region

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.46
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.967

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TNFRSF1BNM_001066.3 linkuse as main transcriptc.554G>C p.Cys185Ser missense_variant, splice_region_variant 6/10 ENST00000376259.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNFRSF1BENST00000376259.7 linkuse as main transcriptc.554G>C p.Cys185Ser missense_variant, splice_region_variant 6/101 NM_001066.3 P1P20333-1
TNFRSF1BENST00000492361.1 linkuse as main transcriptn.543G>C splice_region_variant, non_coding_transcript_exon_variant 5/91
TNFRSF1BENST00000489921.1 linkuse as main transcriptn.266G>C splice_region_variant, non_coding_transcript_exon_variant 3/33

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248328
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134314
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000893
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1460780
Hom.:
0
Cov.:
32
AF XY:
0.00000551
AC XY:
4
AN XY:
726604
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMay 21, 2024The c.554G>C (p.C185S) alteration is located in exon 6 (coding exon 6) of the TNFRSF1B gene. This alteration results from a G to C substitution at nucleotide position 554, causing the cysteine (C) at amino acid position 185 to be replaced by a serine (S). 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
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.33
D
BayesDel_noAF
Pathogenic
0.24
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.82
D
Eigen
Uncertain
0.56
Eigen_PC
Uncertain
0.39
FATHMM_MKL
Uncertain
0.85
D
LIST_S2
Benign
0.71
T
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.97
D
MetaSVM
Uncertain
-0.0070
T
MutationAssessor
Pathogenic
4.0
H
MutationTaster
Benign
0.98
D
PrimateAI
Benign
0.47
T
PROVEAN
Pathogenic
-8.1
D
REVEL
Uncertain
0.55
Sift
Pathogenic
0.0
D
Sift4G
Benign
1.0
T
Polyphen
1.0
D
Vest4
0.81
MutPred
0.71
Gain of glycosylation at C185 (P = 0.0166);
MVP
0.92
MPC
1.2
ClinPred
1.0
D
GERP RS
4.0
Varity_R
0.96
gMVP
0.98

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs757100808; hg19: chr1-12252922; API