rs3093664

Variant names:

• chr6-31576865-A-G
• rs3093664
• NM_000594.4:c.280+51A>G

Variant summary

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

The NM_000594.4(TNF):​c.280+51A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0749 in 1,601,486 control chromosomes in the GnomAD database, including 4,918 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 0.077 (478 hom., cov: 32)
  • Exomes 𝑓: 0.075 (4440 hom.)
• Consequence: TNF NM_000594.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.141

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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.083 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNF	NM_000594.4	c.280+51A>G		intron_variant	Intron 3 of 3	ENST00000449264.3	NP_000585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNF	ENST00000449264.3	c.280+51A>G		intron_variant	Intron 3 of 3	1	NM_000594.4	ENSP00000398698.2
TNF	ENST00000699334.1	c.*12+51A>G		intron_variant	Intron 2 of 2			ENSP00000514308.1

Frequencies

GnomAD3 genomes AF: 0.0766 AC: 11644 AN: 151942 Hom.: 474 Cov.: 32

Gnomad AFR AF: 0.0848

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.0606

Gnomad ASJ AF: 0.119

Gnomad EAS AF: 0.0315

Gnomad SAS AF: 0.0756

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0792

Gnomad OTH AF: 0.0788

GnomAD3 exomes AF: 0.0690 AC: 16966 AN: 245920 Hom.: 689 AF XY: 0.0700 AC XY: 9391 AN XY: 134074

Gnomad AFR exome AF: 0.0854

Gnomad AMR exome AF: 0.0538

Gnomad ASJ exome AF: 0.119

Gnomad EAS exome AF: 0.0283

Gnomad SAS exome AF: 0.0681

Gnomad FIN exome AF: 0.0428

Gnomad NFE exome AF: 0.0791

Gnomad OTH exome AF: 0.0687

GnomAD4 exome AF: 0.0748 AC: 108355 AN: 1449426 Hom.: 4440 Cov.: 28 AF XY: 0.0746 AC XY: 53856 AN XY: 721936

Gnomad4 AFR exome AF: 0.0854

Gnomad4 AMR exome AF: 0.0561

Gnomad4 ASJ exome AF: 0.122

Gnomad4 EAS exome AF: 0.0232

Gnomad4 SAS exome AF: 0.0689

Gnomad4 FIN exome AF: 0.0453

Gnomad4 NFE exome AF: 0.0773

Gnomad4 OTH exome AF: 0.0831

GnomAD4 genome AF: 0.0768 AC: 11671 AN: 152060 Hom.: 478 Cov.: 32 AF XY: 0.0752 AC XY: 5588 AN XY: 74342

Gnomad4 AFR AF: 0.0853

Gnomad4 AMR AF: 0.0606

Gnomad4 ASJ AF: 0.119

Gnomad4 EAS AF: 0.0315

Gnomad4 SAS AF: 0.0748

Gnomad4 FIN AF: 0.0459

Gnomad4 NFE AF: 0.0792

Gnomad4 OTH AF: 0.0779

Alfa AF: 0.0783 Hom.: 120

Bravo AF: 0.0788

Asia WGS AF: 0.0750 AC: 260 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.0
DANN	Benign	0.55

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: rs3093664; hg19: chr6-31544642;