1-12191046-G-A

Variant names:

• chr1-12191046-G-A
• NM_001066.3:c.268G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001066.3(TNFRSF1B):​c.268G>A​(p.Val90Ile) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar 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: -0.473

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051627964).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3	c.268G>A	p.Val90Ile	missense_variant	Exon 3 of 10	ENST00000376259.7	NP_001057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1B	ENST00000376259.7	c.268G>A	p.Val90Ile	missense_variant	Exon 3 of 10	1	NM_001066.3	ENSP00000365435.3
TNFRSF1B	ENST00000536782.2	c.268G>A	p.Val90Ile	missense_variant	Exon 3 of 5	1		ENSP00000440425.1
TNFRSF1B	ENST00000492361.1	n.257G>A		non_coding_transcript_exon_variant	Exon 2 of 9	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 08, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.268G>A (p.V90I) alteration is located in exon 3 (coding exon 3) of the TNFRSF1B gene. This alteration results from a G to A substitution at nucleotide position 268, causing the valine (V) at amino acid position 90 to be replaced by an isoleucine (I). 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	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	3.4
DANN	Benign	0.79
DEOGEN2	Benign	0.26	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.017	N
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.067	D
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	0.81	.;L
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.18	N;N
REVEL	Benign	0.095
Sift	Benign	0.23	T;T
Sift4G	Benign	0.44	T;T
Polyphen		0.016	.;B
Vest4		0.088
MutPred		0.54		Loss of disorder (P = 0.0947);Loss of disorder (P = 0.0947);
MVP		0.28
MPC		0.31
ClinPred		0.032	T
GERP RS		-2.8
Varity_R		0.068
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: chr1-12251103;