dbSNP rs361525: TNF:c.-418G>A (chr6-31575324-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000594.4(TNF):c.-418G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.049 in 486,092 control chromosomes in the GnomAD database, including 705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.047 ( 188 hom., cov: 31)

Exomes 𝑓: 0.050 ( 517 hom. )

Consequence

TNF
NM_000594.4 upstream_gene

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:2

Conservation

PhyloP100: -0.395

Variant links:

Genes affected

TNF (HGNC:11892): (tumor necrosis factor) This gene encodes a multifunctional proinflammatory cytokine that belongs to the tumor necrosis factor (TNF) superfamily. This cytokine is mainly secreted by macrophages. It can bind to, and thus functions through its receptors TNFRSF1A/TNFR1 and TNFRSF1B/TNFBR. This cytokine is involved in the regulation of a wide spectrum of biological processes including cell proliferation, differentiation, apoptosis, lipid metabolism, and coagulation. This cytokine has been implicated in a variety of diseases, including autoimmune diseases, insulin resistance, psoriasis, rheumatoid arthritis ankylosing spondylitis, tuberculosis, autosomal dominant polycystic kidney disease, and cancer. Mutations in this gene affect susceptibility to cerebral malaria, septic shock, and Alzheimer disease. Knockout studies in mice also suggested the neuroprotective function of this cytokine. [provided by RefSeq, Aug 2020]

TNF links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0588 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNF	NM_000594.4 link	c.-418G>A		upstream_gene_variant		ENST00000449264.3	NP_000585.2	P01375Q5STB3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNF	ENST00000449264.3 link	c.-418G>A		upstream_gene_variant		1	NM_000594.4	ENSP00000398698.2		P01375

Frequencies

GnomAD3 genomes

AF:

0.0468

AC:

7114

AN:

152078

Hom.:

187

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0400

Gnomad AMI

AF:

0.154

Gnomad AMR

AF:

0.0504

Gnomad ASJ

AF:

0.0700

Gnomad EAS

AF:

0.0277

Gnomad SAS

AF:

0.0655

Gnomad FIN

AF:

0.0135

Gnomad MID

AF:

0.0633

Gnomad NFE

AF:

0.0522

Gnomad OTH

AF:

0.0650

GnomAD4 exome

AF:

0.0500

AC:

16688

AN:

333896

Hom.:

517

AF XY:

0.0507

AC XY:

9536

AN XY:

188190

show subpopulations

Gnomad4 AFR exome

AF:

0.0408

Gnomad4 AMR exome

AF:

0.0506

Gnomad4 ASJ exome

AF:

0.0745

Gnomad4 EAS exome

AF:

0.0235

Gnomad4 SAS exome

AF:

0.0590

Gnomad4 FIN exome

AF:

0.0171

Gnomad4 NFE exome

AF:

0.0500

Gnomad4 OTH exome

AF:

0.0524

GnomAD4 genome

AF:

0.0468

AC:

7129

AN:

152196

Hom.:

188

Cov.:

AF XY:

0.0463

AC XY:

3443

AN XY:

74418

show subpopulations

Gnomad4 AFR

AF:

0.0404

Gnomad4 AMR

AF:

0.0504

Gnomad4 ASJ

AF:

0.0700

Gnomad4 EAS

AF:

0.0278

Gnomad4 SAS

AF:

0.0648

Gnomad4 FIN

AF:

0.0135

Gnomad4 NFE

AF:

0.0521

Gnomad4 OTH

AF:

0.0643

Alfa

AF:

0.0530

Hom.:

272

Bravo

AF:

0.0484

Asia WGS

AF:

0.0440

AC:

154

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Susceptibility to severe coronavirus disease (COVID-19)

Uncertain:1

Feb 09, 2021

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Susceptibility to severe coronavirus disease (COVID-19) due to high plasma levels of TNF, TNFR, and/or TNFR5

Uncertain:1

Aug 07, 2021

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

Differences in plasma levels of TNFR2 according to genotypes -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

DANN

Benign

0.84

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over