rs3093662

Variant names:

• chr6-31576412-A-G
• rs3093662
• NM_000594.4:c.187-122A>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.187-122A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.069 in 916,376 control chromosomes in the GnomAD database, including 2,659 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 0.072 (444 hom., cov: 31)
  • Exomes 𝑓: 0.068 (2215 hom.)
• Consequence: TNF NM_000594.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31
• Publications: 177 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.076 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.187-122A>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.187-122A>G		intron	N/A	ENSP00000398698.2	P01375
	TNF	ENST00000699334.1		c.187-355A>G		intron	N/A	ENSP00000514308.1	A0A8V8TNL2

Frequencies

GnomAD3 genomes AF: 0.0718 AC: 10920 AN: 152064 Hom.: 440 Cov.: 31

Gnomad AFR AF: 0.0778

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.0740

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.0283

Gnomad SAS AF: 0.0777

Gnomad FIN AF: 0.0153

Gnomad MID AF: 0.150

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.0956

GnomAD4 exome AF: 0.0684 AC: 52241 AN: 764194 Hom.: 2215 AF XY: 0.0689 AC XY: 27517 AN XY: 399246

African (AFR) AF: 0.0765 AC: 1443 AN: 18864

American (AMR) AF: 0.0715 AC: 2133 AN: 29830

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 2370 AN: 16716

East Asian (EAS) AF: 0.0216 AC: 789 AN: 36510

South Asian (SAS) AF: 0.0729 AC: 4343 AN: 59614

European-Finnish (FIN) AF: 0.0209 AC: 904 AN: 43346

Middle Eastern (MID) AF: 0.113 AC: 375 AN: 3310

European-Non Finnish (NFE) AF: 0.0712 AC: 36969 AN: 519154

Other (OTH) AF: 0.0791 AC: 2915 AN: 36850

GnomAD4 genome AF: 0.0719 AC: 10945 AN: 152182 Hom.: 444 Cov.: 31 AF XY: 0.0699 AC XY: 5200 AN XY: 74400

African (AFR) AF: 0.0783 AC: 3247 AN: 41490

American (AMR) AF: 0.0739 AC: 1130 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 479 AN: 3464

East Asian (EAS) AF: 0.0284 AC: 147 AN: 5178

South Asian (SAS) AF: 0.0770 AC: 371 AN: 4820

European-Finnish (FIN) AF: 0.0153 AC: 163 AN: 10626

Middle Eastern (MID) AF: 0.158 AC: 46 AN: 292

European-Non Finnish (NFE) AF: 0.0734 AC: 4992 AN: 68000

Other (OTH) AF: 0.0946 AC: 200 AN: 2114

Alfa AF: 0.0736 Hom.: 1883

Bravo AF: 0.0767

Asia WGS AF: 0.0580 AC: 202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.44
DANN	Benign	0.67
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3093662; hg19: chr6-31544189;