1-12188881-G-A

Variant names:

• chr1-12188881-G-A
• NM_001066.3:c.164G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001066.3(TNFRSF1B):​c.164G>A​(p.Ser55Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,144 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TNFRSF1B NM_001066.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.62

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2706555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3	c.164G>A	p.Ser55Asn	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.164G>A	p.Ser55Asn	missense_variant	Exon 2 of 10	1	NM_001066.3	ENSP00000365435.3
TNFRSF1B	ENST00000536782.2	c.164G>A	p.Ser55Asn	missense_variant	Exon 2 of 5	1		ENSP00000440425.1
TNFRSF1B	ENST00000492361.1	n.168-2076G>A		intron_variant	Intron 1 of 8	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461144 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726866

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.164G>A (p.S55N) alteration is located in exon 2 (coding exon 2) of the TNFRSF1B gene. This alteration results from a G to A substitution at nucleotide position 164, causing the serine (S) at amino acid position 55 to be replaced by an asparagine (N). 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	0.23
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.39	.;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.27	T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.7	.;L
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.27
Sift	Benign	0.14	T;T
Sift4G	Benign	0.42	T;D
Polyphen		0.60	.;P
Vest4		0.26
MutPred		0.46		Loss of disorder (P = 0.0542);Loss of disorder (P = 0.0542);
MVP		0.75
MPC		0.88
ClinPred		0.48	T
GERP RS		0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.065
gMVP		0.60

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: chr1-12248938;