Genetic Variant TNFRSF21:p.Pro520Arg (chr6-47234849-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014452.5(TNFRSF21):c.1559C>G(p.Pro520Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000746 in 1,340,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P520L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.5e-7 ( 0 hom. )

Consequence

TNFRSF21
NM_014452.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.91

Publications

0 publications found

Variant links:

Genes affected

TNFRSF21 (HGNC:13469): (TNF receptor superfamily member 21) This gene encodes a member of the tumor necrosis factor receptor superfamily. The encoded protein activates nuclear factor kappa-B and mitogen-activated protein kinase 8 (also called c-Jun N-terminal kinase 1), and induces cell apoptosis. Through its death domain, the encoded receptor interacts with tumor necrosis factor receptor type 1-associated death domain (TRADD) protein, which is known to mediate signal transduction of tumor necrosis factor receptors. Knockout studies in mice suggest that this gene plays a role in T-helper cell activation, and may be involved in inflammation and immune regulation. [provided by RefSeq, Jul 2013]

TNFRSF21 Gene-Disease associations (from GenCC):

myopia
Inheritance: AD Classification: LIMITED Submitted by: PanelApp Australia

TNFRSF21 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25367028).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014452.5. 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
	TNFRSF21	NM_014452.5	MANE Select	c.1559C>G	p.Pro520Arg	missense	Exon 5 of 6	NP_055267.1	O75509

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNFRSF21	ENST00000296861.2	TSL:1 MANE Select	c.1559C>G	p.Pro520Arg	missense	Exon 5 of 6	ENSP00000296861.2	O75509
TNFRSF21	ENST00000877798.1		c.1637C>G	p.Pro546Arg	missense	Exon 6 of 7	ENSP00000547857.1
TNFRSF21	ENST00000952535.1		c.1064C>G	p.Pro355Arg	missense	Exon 4 of 5	ENSP00000622594.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.46e-7

AC:

AN:

1340434

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

658054

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27602

American (AMR)

AF:

0.00

AC:

AN:

22302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23062

East Asian (EAS)

AF:

0.00

AC:

AN:

32088

South Asian (SAS)

AF:

0.00

AC:

AN:

68756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49962

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4376

European-Non Finnish (NFE)

AF:

9.46e-7

AC:

AN:

1056870

Other (OTH)

AF:

0.00

AC:

AN:

55416

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.0023

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

Eigen

Benign

-0.083

Eigen_PC

Benign

0.038

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.79

M_CAP

Benign

0.051

MetaRNN

Benign

0.25

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.81

PhyloP100

3.9

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.8

REVEL

Benign

0.13

Sift

Uncertain

0.0010

Sift4G

Benign

0.090

Polyphen

0.29

Vest4

0.51

MutPred

0.16

Loss of glycosylation at P520 (P = 0.0134)

MVP

0.21

MPC

0.62

ClinPred

0.78

GERP RS

4.8

Varity_R

0.093

gMVP

0.50

Mutation Taster

=78/22

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over