6-47234849-G-C

Variant names:

• chr6-47234849-G-C
• rs770508831
• NM_014452.5:c.1559C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.91
• 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: 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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF21	NM_014452.5	c.1559C>G	p.Pro520Arg	missense_variant	Exon 5 of 6	ENST00000296861.2	NP_055267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFRSF21	ENST00000296861.2	c.1559C>G	p.Pro520Arg	missense_variant	Exon 5 of 6	1	NM_014452.5	ENSP00000296861.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.46e-7 AC: 1 AN: 1340434 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 658054

African (AFR) AF: 0.00 AC: 0 AN: 27602

American (AMR) AF: 0.00 AC: 0 AN: 22302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23062

East Asian (EAS) AF: 0.00 AC: 0 AN: 32088

South Asian (SAS) AF: 0.00 AC: 0 AN: 68756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4376

European-Non Finnish (NFE) AF: 9.46e-7 AC: 1 AN: 1056870

Other (OTH) AF: 0.00 AC: 0 AN: 55416

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.0023	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.083
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.9
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.090	T
Polyphen		0.29	B
Vest4		0.51
MutPred		0.16		Loss of glycosylation at P520 (P = 0.0134);
MVP		0.21
MPC		0.62
ClinPred		0.78	D
GERP RS		4.8
Varity_R		0.093
gMVP		0.50
Mutation Taster		=78/22	polymorphism

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: rs770508831; hg19: chr6-47202585;