rs3093661

chr6-31575981-G-Achr6-31575981-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000594.4(TNF):c.186+54G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,423,414 control chromosomes in the GnomAD database, including 1,262 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.036 (104 hom., cov: 31)
  • Exomes 𝑓: 0.039 (1158 hom.)
• Consequence: TNF NM_000594.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.482

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNF	NM_000594.4	c.186+54G>A		intron_variant		ENST00000449264.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNF	ENST00000449264.3	c.186+54G>A		intron_variant		1	NM_000594.4	P1
TNF	ENST00000699334.1	c.186+54G>A		intron_variant

Frequencies

GnomAD3 genomes AF: 0.0358 AC: 5442 AN: 152106 Hom.: 101 Cov.: 31

Gnomad AFR AF: 0.0316

Gnomad AMI AF: 0.153

Gnomad AMR AF: 0.0341

Gnomad ASJ AF: 0.0473

Gnomad EAS AF: 0.0276

Gnomad SAS AF: 0.0628

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0388

Gnomad OTH AF: 0.0407

GnomAD4 exome AF: 0.0395 AC: 50163 AN: 1271190 Hom.: 1158 AF XY: 0.0396 AC XY: 24600 AN XY: 620858

Gnomad4 AFR exome AF: 0.0291

Gnomad4 AMR exome AF: 0.0325

Gnomad4 ASJ exome AF: 0.0487

Gnomad4 EAS exome AF: 0.0208

Gnomad4 SAS exome AF: 0.0572

Gnomad4 FIN exome AF: 0.0144

Gnomad4 NFE exome AF: 0.0404

Gnomad4 OTH exome AF: 0.0421

GnomAD4 genome AF: 0.0359 AC: 5460 AN: 152224 Hom.: 104 Cov.: 31 AF XY: 0.0357 AC XY: 2661 AN XY: 74438

Gnomad4 AFR AF: 0.0320

Gnomad4 AMR AF: 0.0342

Gnomad4 ASJ AF: 0.0473

Gnomad4 EAS AF: 0.0276

Gnomad4 SAS AF: 0.0620

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.0388

Gnomad4 OTH AF: 0.0403

Alfa AF: 0.0320 Hom.: 84

Bravo AF: 0.0365

Asia WGS AF: 0.0420 AC: 147 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	6.4
Dann	Benign	0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs3093661; hg19: chr6-31543758;