1-12188885-A-G

Variant names:

• chr1-12188885-A-G
• rs945439
• NM_001066.3:c.168A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_001066.3(TNFRSF1B):​c.168A>G​(p.Lys56Lys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.231 in 1,612,264 control chromosomes in the GnomAD database, including 44,356 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.22 (3713 hom., cov: 33)
  • Exomes 𝑓: 0.23 (40643 hom.)
• Consequence: TNFRSF1B NM_001066.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.74
• Publications: 23 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP7: Synonymous conserved (PhyloP=1.74 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.244 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3	c.168A>G	p.Lys56Lys	synonymous_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.168A>G	p.Lys56Lys	synonymous_variant	Exon 2 of 10	1	NM_001066.3	ENSP00000365435.3
TNFRSF1B	ENST00000536782.2	c.168A>G	p.Lys56Lys	synonymous_variant	Exon 2 of 5	1		ENSP00000440425.1
TNFRSF1B	ENST00000492361.1	n.168-2072A>G		intron_variant	Intron 1 of 8	1

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33146 AN: 152060 Hom.: 3702 Cov.: 33

Gnomad AFR AF: 0.213

Gnomad AMI AF: 0.210

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.264

Gnomad EAS AF: 0.155

Gnomad SAS AF: 0.255

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.238

Gnomad OTH AF: 0.211

GnomAD2 exomes AF: 0.215 AC: 53808 AN: 249760 AF XY: 0.221

Gnomad AFR exome AF: 0.218

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.158

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.220

GnomAD4 exome AF: 0.233 AC: 339913 AN: 1460086 Hom.: 40643 Cov.: 33 AF XY: 0.234 AC XY: 170043 AN XY: 726282

African (AFR) AF: 0.220 AC: 7354 AN: 33450

American (AMR) AF: 0.126 AC: 5598 AN: 44590

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 6977 AN: 26080

East Asian (EAS) AF: 0.141 AC: 5577 AN: 39624

South Asian (SAS) AF: 0.261 AC: 22433 AN: 86084

European-Finnish (FIN) AF: 0.204 AC: 10800 AN: 53010

Middle Eastern (MID) AF: 0.258 AC: 1485 AN: 5758

European-Non Finnish (NFE) AF: 0.239 AC: 265883 AN: 1111166

Other (OTH) AF: 0.229 AC: 13806 AN: 60324

GnomAD4 genome AF: 0.218 AC: 33188 AN: 152178 Hom.: 3713 Cov.: 33 AF XY: 0.215 AC XY: 15982 AN XY: 74414

African (AFR) AF: 0.214 AC: 8892 AN: 41528

American (AMR) AF: 0.153 AC: 2340 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.264 AC: 917 AN: 3468

East Asian (EAS) AF: 0.155 AC: 804 AN: 5172

South Asian (SAS) AF: 0.256 AC: 1235 AN: 4824

European-Finnish (FIN) AF: 0.203 AC: 2147 AN: 10602

Middle Eastern (MID) AF: 0.252 AC: 74 AN: 294

European-Non Finnish (NFE) AF: 0.238 AC: 16148 AN: 67974

Other (OTH) AF: 0.209 AC: 441 AN: 2108

Alfa AF: 0.229 Hom.: 9553

Bravo AF: 0.212

Asia WGS AF: 0.181 AC: 633 AN: 3478

EpiCase AF: 0.234

EpiControl AF: 0.236

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	5.5
DANN	Benign	0.69
PhyloP100		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Mutation Taster		=100/0	polymorphism (auto)

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: rs945439; hg19: chr1-12248942; COSMIC: COSV66163686; COSMIC: COSV66163686;