1-12192870-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001066.3(TNFRSF1B):c.559G>A(p.Val187Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,613,408 control chromosomes in the GnomAD database, including 38 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 0.0086 ( 20 hom., cov: 33)

Exomes 𝑓: 0.00098 ( 18 hom. )

Consequence

TNFRSF1B
NM_001066.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.801

Publications

8 publications found

Variant links:

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]

TNFRSF1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0032384992).

BP6

Variant 1-12192870-G-A is Benign according to our data. Variant chr1-12192870-G-A is described in ClinVar as [Benign]. Clinvar id is 734527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00862 (1313/152250) while in subpopulation AFR AF = 0.0302 (1255/41522). AF 95% confidence interval is 0.0288. There are 20 homozygotes in GnomAd4. There are 607 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 20 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF1B	NM_001066.3 link	c.559G>A	p.Val187Met	missense_variant	Exon 6 of 10	ENST00000376259.7	NP_001057.1	P20333-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFRSF1B	ENST00000376259.7 link	c.559G>A	p.Val187Met	missense_variant	Exon 6 of 10	1	NM_001066.3	ENSP00000365435.3	P20333-1
TNFRSF1B	ENST00000492361.1 link	n.548G>A		non_coding_transcript_exon_variant	Exon 5 of 9	1
TNFRSF1B	ENST00000489921.1 link	n.271G>A		non_coding_transcript_exon_variant	Exon 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.00860

AC:

1309

AN:

152132

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0302

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00382

GnomAD2 exomes

AF:

0.00224

AC:

557

AN:

249072

AF XY:

0.00169

show subpopulations

Gnomad AFR exome

AF:

0.0286

Gnomad AMR exome

AF:

0.00191

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000196

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.000979

AC:

1431

AN:

1461158

Hom.:

Cov.:

AF XY:

0.000850

AC XY:

618

AN XY:

726796

show subpopulations

African (AFR)

AF:

0.0324

AC:

1084

AN:

33468

American (AMR)

AF:

0.00230

AC:

103

AN:

44688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26090

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000186

AC:

AN:

86194

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53278

Middle Eastern (MID)

AF:

0.00121

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

1111630

Other (OTH)

AF:

0.00204

AC:

123

AN:

60364

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

161

242

322

403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00862

AC:

1313

AN:

152250

Hom.:

Cov.:

AF XY:

0.00816

AC XY:

607

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0302

AC:

1255

AN:

41522

American (AMR)

AF:

0.00281

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000207

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000882

AC:

AN:

68014

Other (OTH)

AF:

0.00378

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

134

201

268

335

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00325

Hom.:

Bravo

AF:

0.00978

ESP6500AA

AF:

0.0256

AC:

113

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00267

AC:

324

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000164

EpiControl

AF:

0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.68

CADD

Benign

1.2

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.17

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.81

MetaRNN

Benign

0.0032

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.85

PhyloP100

-0.80

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.29

REVEL

Benign

0.18

Sift

Benign

0.069

Sift4G

Benign

0.095

Polyphen

0.096

Vest4

0.084

MVP

0.51

MPC

0.34

ClinPred

0.0020

GERP RS

-4.5

Varity_R

0.10

gMVP

0.21

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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1-12192870-G-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over