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 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF21	NM_014452.5 link	c.1582G>A	p.Ala528Thr	missense_variant	Exon 5 of 6	ENST00000296861.2	NP_055267.1	O75509A0A024RD71

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF21	ENST00000296861.2 link	c.1582G>A	p.Ala528Thr	missense_variant	Exon 5 of 6	1	NM_014452.5	ENSP00000296861.2		O75509

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

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

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 v4.3

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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6-47234826-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over