dbSNP rs2298212: TNFRSF4:c.634+25C>T (chr1-1211917-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003327.4(TNFRSF4):c.634+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0905 in 1,517,954 control chromosomes in the GnomAD database, including 6,663 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.081 ( 595 hom., cov: 33)

Exomes 𝑓: 0.092 ( 6068 hom. )

Consequence

TNFRSF4
NM_003327.4 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.135

Publications

11 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: Orphanet, PanelApp Australia, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics

TNFRSF4 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 (BayesDel_noAF=-0.84).

BP6

Variant 1-1211917-G-A is Benign according to our data. Variant chr1-1211917-G-A is described in ClinVar as Benign. ClinVar VariationId is 1168340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003327.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNFRSF4	NM_003327.4	MANE Select	c.634+25C>T		intron	N/A	NP_003318.1	P43489
	TNFRSF4	NM_001410709.1		c.634+25C>T		intron	N/A	NP_001397638.1	A0A8V8TQH5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF4	ENST00000379236.4	TSL:1 MANE Select	c.634+25C>T		intron	N/A	ENSP00000368538.3	P43489
TNFRSF4	ENST00000699971.1		c.659C>T	p.Ala220Val	missense	Exon 5 of 6	ENSP00000514728.1	A0A8V8TP52
TNFRSF4	ENST00000699974.1		c.634+25C>T		intron	N/A	ENSP00000514730.1	A0A8V8TQH5

Frequencies

GnomAD3 genomes

AF:

0.0811

AC:

12336

AN:

152026

Hom.:

594

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0620

Gnomad AMI

AF:

0.101

Gnomad AMR

AF:

0.0541

Gnomad ASJ

AF:

0.0718

Gnomad EAS

AF:

0.147

Gnomad SAS

AF:

0.0834

Gnomad FIN

AF:

0.0924

Gnomad MID

AF:

0.0759

Gnomad NFE

AF:

0.0925

Gnomad OTH

AF:

0.0728

GnomAD2 exomes

AF:

0.0834

AC:

10924

AN:

130920

AF XY:

0.0839

show subpopulations

Gnomad AFR exome

AF:

0.0627

Gnomad AMR exome

AF:

0.0460

Gnomad ASJ exome

AF:

0.0694

Gnomad EAS exome

AF:

0.144

Gnomad FIN exome

AF:

0.0956

Gnomad NFE exome

AF:

0.0890

Gnomad OTH exome

AF:

0.0836

GnomAD4 exome

AF:

0.0916

AC:

125046

AN:

1365812

Hom.:

6068

Cov.:

AF XY:

0.0911

AC XY:

61232

AN XY:

672032

show subpopulations

African (AFR)

AF:

0.0617

AC:

1899

AN:

30782

American (AMR)

AF:

0.0481

AC:

1439

AN:

29932

Ashkenazi Jewish (ASJ)

AF:

0.0704

AC:

1578

AN:

22406

East Asian (EAS)

AF:

0.146

AC:

5371

AN:

36898

South Asian (SAS)

AF:

0.0813

AC:

6061

AN:

74594

European-Finnish (FIN)

AF:

0.0957

AC:

3868

AN:

40410

Middle Eastern (MID)

AF:

0.0781

AC:

412

AN:

5278

European-Non Finnish (NFE)

AF:

0.0928

AC:

99181

AN:

1068926

Other (OTH)

AF:

0.0925

AC:

5237

AN:

56586

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

6848

13696

20543

27391

34239

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3766

7532

11298

15064

18830

<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:

0.0811

AC:

12335

AN:

152142

Hom.:

595

Cov.:

AF XY:

0.0821

AC XY:

6108

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0620

AC:

2576

AN:

41538

American (AMR)

AF:

0.0540

AC:

827

AN:

15312

Ashkenazi Jewish (ASJ)

AF:

0.0718

AC:

249

AN:

3468

East Asian (EAS)

AF:

0.148

AC:

761

AN:

5140

South Asian (SAS)

AF:

0.0824

AC:

398

AN:

4828

European-Finnish (FIN)

AF:

0.0924

AC:

980

AN:

10610

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0924

AC:

6280

AN:

67930

Other (OTH)

AF:

0.0716

AC:

151

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

584

1168

1753

2337

2921

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.0883

Hom.:

125

Bravo

AF:

0.0786

Asia WGS

AF:

0.102

AC:

357

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Combined immunodeficiency due to OX40 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

3.7

(source)

DANN

Benign

0.45

PhyloP100

-0.14

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over