Genetic Variant TNFRSF4:p.Glu266Lys (chr1-1211593-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003327.4(TNFRSF4):c.796G>A(p.Glu266Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000146 in 1,374,222 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. E266E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

TNFRSF4
NM_003327.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.752

Publications

0 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF4	NM_003327.4 link	c.796G>A	p.Glu266Lys	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.796G>A	p.Glu266Lys	missense_variant	Exon 7 of 7	1	NM_003327.4	ENSP00000368538.3		P43489

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1374222

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

676088

show subpopulations

African (AFR)

AF:

0.0000339

AC:

AN:

29492

American (AMR)

AF:

0.00

AC:

AN:

30444

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20868

East Asian (EAS)

AF:

0.0000271

AC:

AN:

36940

South Asian (SAS)

AF:

0.00

AC:

AN:

73810

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50324

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5372

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1070542

Other (OTH)

AF:

0.00

AC:

AN:

56430

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Combined immunodeficiency due to OX40 deficiency

Uncertain:1

Nov 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1478848). This variant has not been reported in the literature in individuals affected with TNFRSF4-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 266 of the TNFRSF4 protein (p.Glu266Lys). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.56

BayesDel_addAF

Benign

-0.00029

BayesDel_noAF

Benign

-0.24

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.38

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.81

M_CAP

Pathogenic

0.33

MetaRNN

Uncertain

0.43

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

1.1

PhyloP100

0.75

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.5

REVEL

Benign

0.19

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.37

MutPred

0.29

Gain of ubiquitination at E266 (P = 0.0011);

MVP

0.80

MPC

0.68

ClinPred

0.91

GERP RS

3.2

Varity_R

0.70

gMVP

0.72

Mutation Taster

=88/12

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over