1-12192919-C-T

Variant names:

• chr1-12192919-C-T
• rs199873050
• NM_001066.3:c.608C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001066.3(TNFRSF1B):​c.608C>T​(p.Thr203Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000647 in 1,614,182 control chromosomes in the GnomAD database, including 15 homozygotes. 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00067 (14 hom.)
• Consequence: TNFRSF1B NM_001066.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.11
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00282982).
• BP6: Variant 1-12192919-C-T is Benign according to our data. Variant chr1-12192919-C-T is described in ClinVar as [Benign]. Clinvar id is 744556.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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.608C>T	p.Thr203Met	missense_variant	Exon 6 of 10	ENST00000376259.7	NP_001057.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF1B	ENST00000376259.7	c.608C>T	p.Thr203Met	missense_variant	Exon 6 of 10	1	NM_001066.3	ENSP00000365435.3
TNFRSF1B	ENST00000492361.1	n.597C>T		non_coding_transcript_exon_variant	Exon 5 of 9	1
TNFRSF1B	ENST00000489921.1	n.320C>T		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes AF: 0.000460 AC: 70 AN: 152188 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00130 AC: 326 AN: 251100 AF XY: 0.00165

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000666 AC: 973 AN: 1461876 Hom.: 14 Cov.: 34 AF XY: 0.000892 AC XY: 649 AN XY: 727238

African (AFR) AF: 0.0000299 AC: 1 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0101 AC: 871 AN: 86256

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53416

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000387 AC: 43 AN: 1112008

Other (OTH) AF: 0.000894 AC: 54 AN: 60396

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152306 Hom.: 1 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74478

African (AFR) AF: 0.0000241 AC: 1 AN: 41562

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0135 AC: 65 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68020

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000785 Hom.: 0

Bravo AF: 0.000102

ExAC AF: 0.00143 AC: 173

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

May 21, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.18
DANN	Benign	0.75
DEOGEN2	Benign	0.20	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.0086	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.41	N
PhyloP100		-1.1
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.048
Sift	Benign	0.093	T
Sift4G	Benign	0.075	T
Polyphen		0.0070	B
Vest4		0.067
MVP		0.26
MPC		0.36
ClinPred		0.022	T
GERP RS		-8.2
Varity_R		0.012
gMVP		0.27
Mutation Taster		=99/1	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: rs199873050; hg19: chr1-12252976;