Genetic Variant TNFRSF4:c.*150C>A (chr1-1211405-G-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003327.4(TNFRSF4):c.*150C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000182 in 550,018 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000018 ( 0 hom. )

Consequence

TNFRSF4
NM_003327.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.41

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

TNFRSF4 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_003327.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

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.*150C>A		3_prime_UTR	Exon 7 of 7	NP_003318.1	P43489
	TNFRSF4	NM_001410709.1		c.*150C>A		3_prime_UTR	Exon 6 of 6	NP_001397638.1	A0A8V8TQH5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TNFRSF4	ENST00000379236.4	TSL:1 MANE Select	c.*150C>A	3_prime_UTR	Exon 7 of 7	ENSP00000368538.3	P43489
TNFRSF4	ENST00000699971.1		c.*25C>A	3_prime_UTR	Exon 6 of 6	ENSP00000514728.1	A0A8V8TP52
TNFRSF4	ENST00000699974.1		c.*150C>A	3_prime_UTR	Exon 6 of 6	ENSP00000514730.1	A0A8V8TQH5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000182

AC:

AN:

550018

Hom.:

Cov.:

AF XY:

0.00000361

AC XY:

AN XY:

276964

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

11582

American (AMR)

AF:

0.00

AC:

AN:

11452

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12576

East Asian (EAS)

AF:

0.00

AC:

AN:

25146

South Asian (SAS)

AF:

0.00

AC:

AN:

28396

European-Finnish (FIN)

AF:

0.0000294

AC:

AN:

33972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2116

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

396902

Other (OTH)

AF:

0.00

AC:

AN:

27876

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

1.8

(source)

DANN

Benign

0.76

PhyloP100

-2.4

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over