6-47234828-T-C

Variant names:

• chr6-47234828-T-C
• rs144939843
• NM_014452.5:c.1580A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_014452.5(TNFRSF21):​c.1580A>G​(p.Asn527Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,545,374 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00091 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: TNFRSF21 NM_014452.5 missense
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.923
• Publications: 5 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004008323).
• BP6: Variant 6-47234828-T-C is Benign according to our data. Variant chr6-47234828-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 3352684.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 138 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFRSF21	NM_014452.5	c.1580A>G	p.Asn527Ser	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.1580A>G	p.Asn527Ser	missense_variant	Exon 5 of 6	1	NM_014452.5	ENSP00000296861.2

Frequencies

GnomAD3 genomes AF: 0.000908 AC: 138 AN: 152002 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00104

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000887 AC: 151 AN: 170260 AF XY: 0.000921

Gnomad AFR exome AF: 0.000290

Gnomad AMR exome AF: 0.000591

Gnomad ASJ exome AF: 0.00162

Gnomad EAS exome AF: 0.0000904

Gnomad FIN exome AF: 0.000340

Gnomad NFE exome AF: 0.00145

Gnomad OTH exome AF: 0.000732

GnomAD4 exome AF: 0.00114 AC: 1589 AN: 1393254 Hom.: 1 Cov.: 31 AF XY: 0.00112 AC XY: 769 AN XY: 688452

African (AFR) AF: 0.0000333 AC: 1 AN: 30010

American (AMR) AF: 0.000960 AC: 31 AN: 32302

Ashkenazi Jewish (ASJ) AF: 0.00118 AC: 29 AN: 24520

East Asian (EAS) AF: 0.0000855 AC: 3 AN: 35078

South Asian (SAS) AF: 0.0000132 AC: 1 AN: 75930

European-Finnish (FIN) AF: 0.000465 AC: 24 AN: 51626

Middle Eastern (MID) AF: 0.000203 AC: 1 AN: 4922

European-Non Finnish (NFE) AF: 0.00134 AC: 1444 AN: 1081330

Other (OTH) AF: 0.000956 AC: 55 AN: 57536

GnomAD4 genome AF: 0.000907 AC: 138 AN: 152120 Hom.: 0 Cov.: 32 AF XY: 0.000914 AC XY: 68 AN XY: 74380

African (AFR) AF: 0.000289 AC: 12 AN: 41504

American (AMR) AF: 0.00275 AC: 42 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3464

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00104 AC: 71 AN: 67988

Other (OTH) AF: 0.00190 AC: 4 AN: 2108

Alfa AF: 0.000981 Hom.: 0

Bravo AF: 0.00106

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00116 AC: 10

ExAC AF: 0.000752 AC: 91

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TNFRSF21-related condition Benign:1

Jun 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.33
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T
M_CAP	Benign	0.0059	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.34	N
PhyloP100		0.92
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.12
Sift	Benign	0.30	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.20
MVP		0.093
MPC		0.22
ClinPred		0.0058	T
GERP RS		1.1
Varity_R		0.036
gMVP		0.096
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs144939843; hg19: chr6-47202564; COSMIC: COSV99730429;