rs3093665

Variant names:

• chr6-31577614-A-C
• rs3093665
• NM_000594.4:c.*77A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000594.4(TNF):​c.*77A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,563,882 control chromosomes in the GnomAD database, including 472 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 0.025 (56 hom., cov: 32)
  • Exomes 𝑓: 0.020 (416 hom.)
• Consequence: TNF NM_000594.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.325
• Publications: 38 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=-0.78).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0245 (3738/152280) while in subpopulation AFR AF = 0.0359 (1493/41546). AF 95% confidence interval is 0.0344. There are 56 homozygotes in GnomAd4. There are 1723 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 3738 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNF	NM_000594.4	c.*77A>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000449264.3	NP_000585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNF	ENST00000449264.3	c.*77A>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_000594.4	ENSP00000398698.2
TNF	ENST00000699334.1	c.*511A>C		downstream_gene_variant				ENSP00000514308.1

Frequencies

GnomAD3 genomes AF: 0.0245 AC: 3731 AN: 152162 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.0359

Gnomad AMI AF: 0.0329

Gnomad AMR AF: 0.0236

Gnomad ASJ AF: 0.0688

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0193 AC: 4245 AN: 219800 AF XY: 0.0197

Gnomad AFR exome AF: 0.0369

Gnomad AMR exome AF: 0.0194

Gnomad ASJ exome AF: 0.0680

Gnomad EAS exome AF: 0.000238

Gnomad FIN exome AF: 0.00205

Gnomad NFE exome AF: 0.0210

Gnomad OTH exome AF: 0.0242

GnomAD4 exome AF: 0.0201 AC: 28406 AN: 1411602 Hom.: 416 Cov.: 25 AF XY: 0.0203 AC XY: 14251 AN XY: 702078

African (AFR) AF: 0.0359 AC: 1172 AN: 32678

American (AMR) AF: 0.0210 AC: 886 AN: 42126

Ashkenazi Jewish (ASJ) AF: 0.0701 AC: 1793 AN: 25570

East Asian (EAS) AF: 0.000204 AC: 8 AN: 39188

South Asian (SAS) AF: 0.0108 AC: 909 AN: 84272

European-Finnish (FIN) AF: 0.00271 AC: 133 AN: 49050

Middle Eastern (MID) AF: 0.0516 AC: 293 AN: 5682

European-Non Finnish (NFE) AF: 0.0200 AC: 21513 AN: 1074270

Other (OTH) AF: 0.0289 AC: 1699 AN: 58766

GnomAD4 genome AF: 0.0245 AC: 3738 AN: 152280 Hom.: 56 Cov.: 32 AF XY: 0.0231 AC XY: 1723 AN XY: 74460

African (AFR) AF: 0.0359 AC: 1493 AN: 41546

American (AMR) AF: 0.0235 AC: 360 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0688 AC: 239 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5192

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4826

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10618

Middle Eastern (MID) AF: 0.0986 AC: 29 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1445 AN: 68008

Other (OTH) AF: 0.0293 AC: 62 AN: 2114

Alfa AF: 0.0235 Hom.: 220

Bravo AF: 0.0275

Asia WGS AF: 0.0140 AC: 49 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.5
DANN	Benign	0.72
PhyloP100		-0.33
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: rs3093665; hg19: chr6-31545391; COSMIC: COSV69305145; COSMIC: COSV69305145;