Genetic Variant TNFRSF4:c.764-19C>G (chr1-1211644-G-C) – 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_001410709.1(TNFRSF4):c.823C>G(p.Leu275Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000213 in 1,411,086 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 5/5 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L275F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TNFRSF4
NM_001410709.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.251

Publications

1 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: 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=-0.88).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001410709.1. 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.764-19C>G		intron	N/A	NP_003318.1	P43489
	TNFRSF4	NM_001410709.1		c.823C>G	p.Leu275Val	missense	Exon 6 of 6	NP_001397638.1	A0A8V8TQH5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF4	ENST00000379236.4	TSL:1 MANE Select	c.764-19C>G		intron	N/A	ENSP00000368538.3	P43489
TNFRSF4	ENST00000699974.1		c.823C>G	p.Leu275Val	missense	Exon 6 of 6	ENSP00000514730.1	A0A8V8TQH5
TNFRSF4	ENST00000699971.1		c.873-19C>G		intron	N/A	ENSP00000514728.1	A0A8V8TP52

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000977

AC:

AN:

204708

AF XY:

0.0000178

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000130

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000213

AC:

AN:

1411086

Hom.:

Cov.:

AF XY:

0.00000286

AC XY:

AN XY:

698532

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30798

American (AMR)

AF:

0.00

AC:

AN:

35520

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23406

East Asian (EAS)

AF:

0.0000797

AC:

AN:

37644

South Asian (SAS)

AF:

0.00

AC:

AN:

80456

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51386

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5564

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088416

Other (OTH)

AF:

0.00

AC:

AN:

57896

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

1.8

(source)

DANN

Benign

0.59

PhyloP100

-0.25

Mutation Taster

=100/0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over