chr6-47253481-G-T

Variant names:

• chr6-47253481-G-T
• rs777990557
• NM_014452.5:c.1284C>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_014452.5(TNFRSF21):​c.1284C>A​(p.Ser428Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000167 in 1,613,354 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: TNFRSF21 NM_014452.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.75
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF21	NM_014452.5	c.1284C>A	p.Ser428Arg	missense_variant	Exon 4 of 6	ENST00000296861.2	NP_055267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF21	ENST00000296861.2	c.1284C>A	p.Ser428Arg	missense_variant	Exon 4 of 6	1	NM_014452.5	ENSP00000296861.2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250852 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461202 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 726978

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000727 AC: 19 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52742

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1112004

Other (OTH) AF: 0.0000331 AC: 2 AN: 60392

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74316

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 12, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1284C>A (p.S428R) alteration is located in exon 4 (coding exon 4) of the TNFRSF21 gene. This alteration results from a C to A substitution at nucleotide position 1284, causing the serine (S) at amino acid position 428 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.049	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Benign	0.55	N
PhyloP100		3.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.60		Gain of MoRF binding (P = 0.0152);
MVP		0.61
MPC		0.88
ClinPred		0.58	D
GERP RS		6.0
Varity_R		0.47
gMVP		0.37
Mutation Taster		=42/58	disease causing

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

Other links and lift over

dbSNP: rs777990557; hg19: chr6-47221217;