NM_000594.4:c.280+51A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 59 publications found

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000594.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNF	NM_000594.4	MANE Select	c.280+51A>G		intron	N/A	NP_000585.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNF	ENST00000449264.3	TSL:1 MANE Select	c.280+51A>G		intron	N/A	ENSP00000398698.2	P01375
	TNF	ENST00000699334.1		c.*12+51A>G		intron	N/A	ENSP00000514308.1	A0A8V8TNL2

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

GnomAD2 exomes AF: 0.0690 AC: 16966 AN: 245920 AF XY: 0.0700

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 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

African (AFR) AF: 0.0854 AC: 2835 AN: 33198

American (AMR) AF: 0.0561 AC: 2503 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 3180 AN: 26064

East Asian (EAS) AF: 0.0232 AC: 921 AN: 39652

South Asian (SAS) AF: 0.0689 AC: 5926 AN: 86020

European-Finnish (FIN) AF: 0.0453 AC: 2373 AN: 52374

Middle Eastern (MID) AF: 0.0856 AC: 489 AN: 5714

European-Non Finnish (NFE) AF: 0.0773 AC: 85140 AN: 1101764

Other (OTH) AF: 0.0831 AC: 4988 AN: 60012

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

African (AFR) AF: 0.0853 AC: 3538 AN: 41468

American (AMR) AF: 0.0606 AC: 925 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.119 AC: 411 AN: 3466

East Asian (EAS) AF: 0.0315 AC: 163 AN: 5168

South Asian (SAS) AF: 0.0748 AC: 361 AN: 4826

European-Finnish (FIN) AF: 0.0459 AC: 485 AN: 10576

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0792 AC: 5383 AN: 67988

Other (OTH) AF: 0.0779 AC: 164 AN: 2104

Alfa AF: 0.0750 Hom.: 778

Bravo AF: 0.0788

Asia WGS AF: 0.0750 AC: 260 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	4.0
DANN	Benign	0.55
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3093664; hg19: chr6-31544642;