rs17568

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_003327.4(TNFRSF4):c.534G>A(p.Glu178Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.273 in 1,611,028 control chromosomes in the GnomAD database, including 76,346 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.32 ( 9219 hom., cov: 34)

Exomes 𝑓: 0.27 ( 67127 hom. )

Consequence

TNFRSF4
NM_003327.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.00300

Publications

27 publications found

Variant links:

Genes affected

TNFRSF4 (HGNC:11918): (TNF receptor superfamily member 4) The protein encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been shown to activate NF-kappaB through its interaction with adaptor proteins TRAF2 and TRAF5. Knockout studies in mice suggested that this receptor promotes the expression of apoptosis inhibitors BCL2 and BCL2lL1/BCL2-XL, and thus suppresses apoptosis. The knockout studies also suggested the roles of this receptor in CD4+ T cell response, as well as in T cell-dependent B cell proliferation and differentiation. [provided by RefSeq, Jul 2008]

TNFRSF4 Gene-Disease associations (from GenCC):

combined immunodeficiency due to OX40 deficiency
Inheritance: AR, Unknown Classification: SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae)

TNFRSF4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.017).

BP6

Variant 1-1212042-C-T is Benign according to our data. Variant chr1-1212042-C-T is described in ClinVar as Benign. ClinVar VariationId is 403556.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.003 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.731 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF4	NM_003327.4 link	c.534G>A	p.Glu178Glu	synonymous_variant	Exon 5 of 7	ENST00000379236.4	NP_003318.1	P43489

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF4	ENST00000379236.4 link	c.534G>A	p.Glu178Glu	synonymous_variant	Exon 5 of 7	1	NM_003327.4	ENSP00000368538.3		P43489

Frequencies

GnomAD3 genomes

AF:

0.317

AC:

48124

AN:

151944

Hom.:

9189

Cov.:

show subpopulations

Gnomad AFR

AF:

0.394

Gnomad AMI

AF:

0.140

Gnomad AMR

AF:

0.459

Gnomad ASJ

AF:

0.190

Gnomad EAS

AF:

0.751

Gnomad SAS

AF:

0.580

Gnomad FIN

AF:

0.224

Gnomad MID

AF:

0.244

Gnomad NFE

AF:

0.210

Gnomad OTH

AF:

0.301

GnomAD2 exomes

AF:

0.367

AC:

89404

AN:

243526

AF XY:

0.360

show subpopulations

Gnomad AFR exome

AF:

0.396

Gnomad AMR exome

AF:

0.623

Gnomad ASJ exome

AF:

0.182

Gnomad EAS exome

AF:

0.742

Gnomad FIN exome

AF:

0.232

Gnomad NFE exome

AF:

0.212

Gnomad OTH exome

AF:

0.304

GnomAD4 exome

AF:

0.268

AC:

391246

AN:

1458966

Hom.:

67127

Cov.:

AF XY:

0.275

AC XY:

199321

AN XY:

725776

show subpopulations

African (AFR)

AF:

0.403

AC:

13464

AN:

33440

American (AMR)

AF:

0.602

AC:

26779

AN:

44448

Ashkenazi Jewish (ASJ)

AF:

0.186

AC:

4822

AN:

25958

East Asian (EAS)

AF:

0.768

AC:

30450

AN:

39668

South Asian (SAS)

AF:

0.556

AC:

47889

AN:

86058

European-Finnish (FIN)

AF:

0.232

AC:

12117

AN:

52140

Middle Eastern (MID)

AF:

0.280

AC:

1611

AN:

5746

European-Non Finnish (NFE)

AF:

0.212

AC:

236136

AN:

1111228

Other (OTH)

AF:

0.298

AC:

17978

AN:

60280

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

16458

32916

49373

65831

82289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8816

17632

26448

35264

44080

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.317

AC:

48202

AN:

152062

Hom.:

9219

Cov.:

AF XY:

0.326

AC XY:

24241

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.394

AC:

16352

AN:

41464

American (AMR)

AF:

0.460

AC:

7036

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.190

AC:

658

AN:

3470

East Asian (EAS)

AF:

0.751

AC:

3860

AN:

5142

South Asian (SAS)

AF:

0.580

AC:

2802

AN:

4832

European-Finnish (FIN)

AF:

0.224

AC:

2379

AN:

10606

Middle Eastern (MID)

AF:

0.241

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.210

AC:

14262

AN:

67942

Other (OTH)

AF:

0.310

AC:

655

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1585

3170

4755

6340

7925

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.241

Hom.:

2251

Bravo

AF:

0.332

Asia WGS

AF:

0.682

AC:

2366

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Combined immunodeficiency due to OX40 deficiency

Benign:2

Jul 14, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Nov 12, 2018

GeneDx

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

- -

not specified

Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.6

(source)

DANN

Benign

0.68

PhyloP100

0.0030

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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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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