1-12192516-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001066.3(TNFRSF1B):c.543C>T(p.Pro181=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 1,614,050 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (14 hom.)
• Consequence: TNFRSF1B NM_001066.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0300

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 1-12192516-C-T is Benign according to our data. Variant chr1-12192516-C-T is described in ClinVar as [Benign]. Clinvar id is 731198.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00116 (177/152276) while in subpopulation EAS AF= 0.0232 (120/5172). AF 95% confidence interval is 0.0198. There are 1 homozygotes in gnomad4. There are 98 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNFRSF1B	NM_001066.3	c.543C>T	p.Pro181=	synonymous_variant	5/10	ENST00000376259.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNFRSF1B	ENST00000376259.7	c.543C>T	p.Pro181=	synonymous_variant	5/10	1	NM_001066.3	P1
TNFRSF1B	ENST00000492361.1	n.532C>T		non_coding_transcript_exon_variant	4/9	1
TNFRSF1B	ENST00000489921.1	n.255C>T		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152158 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.0233

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00141

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.00247 AC: 622 AN: 251478 Hom.: 5 AF XY: 0.00229 AC XY: 311 AN XY: 135914

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000578

Gnomad ASJ exome AF: 0.00417

Gnomad EAS exome AF: 0.0254

Gnomad SAS exome AF: 0.000261

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.000360

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00100 AC: 1466 AN: 1461774 Hom.: 14 Cov.: 32 AF XY: 0.000989 AC XY: 719 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00379

Gnomad4 EAS exome AF: 0.0249

Gnomad4 SAS exome AF: 0.000209

Gnomad4 FIN exome AF: 0.00236

Gnomad4 NFE exome AF: 0.000135

Gnomad4 OTH exome AF: 0.00132

GnomAD4 genome AF: 0.00116 AC: 177 AN: 152276 Hom.: 1 Cov.: 32 AF XY: 0.00132 AC XY: 98 AN XY: 74446

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.0232

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00141

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000664 Hom.: 0

Bravo AF: 0.00128

Asia WGS AF: 0.00722 AC: 25 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 20, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
Cadd	Benign	8.9
Dann	Benign	0.77

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

Other links and lift over

dbSNP: rs2275415; hg19: chr1-12252573;