rs361525

Variant names:

• chr6-31575324-G-A
• rs361525
• NM_000594.4:c.-418G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: -0.395

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]

ACMG classification

Our verdict: Benign. The variant received -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	c.-418G>A		upstream_gene_variant		ENST00000449264.3	NP_000585.2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 7114 AN: 152078 Hom.: 187 Cov.: 31

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

Gnomad4 AFR exome AF: 0.0408 AC: 399 AN: 9780

Gnomad4 AMR exome AF: 0.0506 AC: 1403 AN: 27734

Gnomad4 ASJ exome AF: 0.0745 AC: 899 AN: 12060

Gnomad4 EAS exome AF: 0.0235 AC: 276 AN: 11738

Gnomad4 SAS exome AF: 0.0590 AC: 3512 AN: 59536

Gnomad4 FIN exome AF: 0.0171 AC: 251 AN: 14712

Gnomad4 NFE exome AF: 0.0500 AC: 8961 AN: 179308

Gnomad4 Remaining exome AF: 0.0524 AC: 859 AN: 16402

GnomAD4 genome AF: 0.0468 AC: 7129 AN: 152196 Hom.: 188 Cov.: 31 AF XY: 0.0463 AC XY: 3443 AN XY: 74418

Gnomad4 AFR AF: 0.0404 AC: 0.0403804 AN: 0.0403804

Gnomad4 AMR AF: 0.0504 AC: 0.0504383 AN: 0.0504383

Gnomad4 ASJ AF: 0.0700 AC: 0.0700288 AN: 0.0700288

Gnomad4 EAS AF: 0.0278 AC: 0.0277992 AN: 0.0277992

Gnomad4 SAS AF: 0.0648 AC: 0.0647572 AN: 0.0647572

Gnomad4 FIN AF: 0.0135 AC: 0.0134855 AN: 0.0134855

Gnomad4 NFE AF: 0.0521 AC: 0.0521416 AN: 0.0521416

Gnomad4 OTH AF: 0.0643 AC: 0.064333 AN: 0.064333

Alfa AF: 0.0497 Hom.: 625

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

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	10
DANN	Benign	0.84

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs361525; hg19: chr6-31543101;