1-1211581-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_003327.4(TNFRSF4):c.808G>A(p.Ala270Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000027 in 1,516,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A270D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000026 ( 0 hom. )

Consequence

TNFRSF4
NM_003327.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.112

Publications

2 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.05843723).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF4	NM_003327.4 link	c.808G>A	p.Ala270Thr	missense_variant	Exon 7 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.808G>A	p.Ala270Thr	missense_variant	Exon 7 of 7	1	NM_003327.4	ENSP00000368538.3		P43489

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000292

AC:

AN:

171232

AF XY:

0.0000436

show subpopulations

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:

0.0000494

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000264

AC:

AN:

1364506

Hom.:

Cov.:

AF XY:

0.0000299

AC XY:

AN XY:

669714

show subpopulations

African (AFR)

AF:

0.0000342

AC:

AN:

29250

American (AMR)

AF:

0.00

AC:

AN:

29262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20250

East Asian (EAS)

AF:

0.0000543

AC:

AN:

36844

South Asian (SAS)

AF:

0.0000139

AC:

AN:

71880

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49940

Middle Eastern (MID)

AF:

0.000563

AC:

AN:

5330

European-Non Finnish (NFE)

AF:

0.0000225

AC:

AN:

1065758

Other (OTH)

AF:

0.0000893

AC:

AN:

55992

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152048

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74272

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41402

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.000193

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67980

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.565

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000529

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000580

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.808G>A (p.A270T) alteration is located in exon 7 (coding exon 7) of the TNFRSF4 gene. This alteration results from a G to A substitution at nucleotide position 808, causing the alanine (A) at amino acid position 270 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Combined immunodeficiency due to OX40 deficiency

Uncertain:1

Oct 18, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 270 of the TNFRSF4 protein (p.Ala270Thr). This variant is present in population databases (rs375419469, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with TNFRSF4-related conditions. ClinVar contains an entry for this variant (Variation ID: 1446419). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.14

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.54

M_CAP

Uncertain

0.11

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.96

MutationAssessor

Benign

1.0

PhyloP100

-0.11

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.75

REVEL

Benign

0.094

Sift

Benign

0.13

Sift4G

Pathogenic

0.0

Polyphen

0.79

Vest4

0.026

MVP

0.55

MPC

0.19

ClinPred

0.054

GERP RS

1.2

Varity_R

0.042

gMVP

0.46

Mutation Taster

=98/2

polymorphism

(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

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1-1211581-C-T

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