Genetic Variant TNFRSF21:p.Ala528Thr (chr6-47234826-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_014452.5(TNFRSF21):c.1582G>A(p.Ala528Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000758 in 1,543,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. A528S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000069 ( 0 hom. )

Consequence

TNFRSF21
NM_014452.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.411

Publications

1 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: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016774535).

BS2

High AC in GnomAd4 at 21 AD gene.

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.1582G>A	p.Ala528Thr	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.1582G>A	p.Ala528Thr	missense	Exon 5 of 6	ENSP00000296861.2	O75509
TNFRSF21	ENST00000877798.1		c.1660G>A	p.Ala554Thr	missense	Exon 6 of 7	ENSP00000547857.1
TNFRSF21	ENST00000952535.1		c.1087G>A	p.Ala363Thr	missense	Exon 4 of 5	ENSP00000622594.1

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

151822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000387

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000997

AC:

AN:

170444

AF XY:

0.000108

show subpopulations

Gnomad AFR exome

AF:

0.000582

Gnomad AMR exome

AF:

0.000148

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000690

AC:

AN:

1391806

Hom.:

Cov.:

AF XY:

0.0000582

AC XY:

AN XY:

687624

show subpopulations

African (AFR)

AF:

0.000234

AC:

AN:

29888

American (AMR)

AF:

0.000187

AC:

AN:

32082

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24492

East Asian (EAS)

AF:

0.00

AC:

AN:

34844

South Asian (SAS)

AF:

0.00

AC:

AN:

75688

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51658

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4932

European-Non Finnish (NFE)

AF:

0.0000759

AC:

AN:

1080718

Other (OTH)

AF:

0.0000174

AC:

AN:

57504

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

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

AF:

0.000138

AC:

AN:

151822

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74140

show subpopulations

African (AFR)

AF:

0.000387

AC:

AN:

41330

American (AMR)

AF:

0.000197

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10540

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

67998

Other (OTH)

AF:

0.00

AC:

AN:

2068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000136

Hom.:

Bravo

AF:

0.000223

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000661

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.47

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.12

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.059

LIST_S2

Benign

0.47

M_CAP

Benign

0.0097

MetaRNN

Benign

0.017

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.34

PhyloP100

-0.41

PrimateAI

Benign

0.24

PROVEAN

Benign

0.19

REVEL

Benign

0.10

Sift

Benign

0.70

Sift4G

Benign

0.76

Polyphen

0.0030

Vest4

0.097

MVP

0.11

MPC

0.27

ClinPred

0.0094

GERP RS

-9.5

Varity_R

0.013

gMVP

0.18

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over