1-12192516-C-T

Variant names:

• chr1-12192516-C-T
• rs2275415
• NM_001066.3:c.543C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001066.3(TNFRSF1B):​c.543C>T​(p.Pro181Pro) 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0300
• Publications: 5 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 -20 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3	c.543C>T	p.Pro181Pro	synonymous_variant	Exon 5 of 10	ENST00000376259.7	NP_001057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1B	ENST00000376259.7	c.543C>T	p.Pro181Pro	synonymous_variant	Exon 5 of 10	1	NM_001066.3	ENSP00000365435.3
TNFRSF1B	ENST00000492361.1	n.532C>T		non_coding_transcript_exon_variant	Exon 4 of 9	1
TNFRSF1B	ENST00000489921.1	n.255C>T		non_coding_transcript_exon_variant	Exon 2 of 3	3
TNFRSF1B	ENST00000536782.2	c.*158C>T		downstream_gene_variant		1		ENSP00000440425.1

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

GnomAD2 exomes AF: 0.00247 AC: 622 AN: 251478 AF XY: 0.00229

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 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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00379 AC: 99 AN: 26136

East Asian (EAS) AF: 0.0249 AC: 990 AN: 39698

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86250

European-Finnish (FIN) AF: 0.00236 AC: 126 AN: 53410

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5738

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1111956

Other (OTH) AF: 0.00132 AC: 80 AN: 60384

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

African (AFR) AF: 0.0000241 AC: 1 AN: 41552

American (AMR) AF: 0.000262 AC: 4 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 9 AN: 3468

East Asian (EAS) AF: 0.0232 AC: 120 AN: 5172

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00141 AC: 15 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000762 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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 20, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	8.9
DANN	Benign	0.77
PhyloP100		0.030
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs2275415; hg19: chr1-12252573;