6-31575324-G-A

Variant names:

• chr6-31575324-G-A
• rs361525
• NM_000594.4:c.-418G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000594.4(TNF):​c.-418G>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.049 in 486,092 control chromosomes in the GnomAD database, including 705 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.047 (188 hom., cov: 31)
  • Exomes 𝑓: 0.050 (517 hom.)
• Consequence: TNF NM_000594.4 upstream_gene
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: -0.395
• Publications: 1241 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).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0588 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNF	NM_000594.4	MANE Select	c.-418G>A		upstream_gene	N/A	NP_000585.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNF	ENST00000449264.3	TSL:1 MANE Select	c.-418G>A		upstream_gene	N/A	ENSP00000398698.2

Frequencies

GnomAD3 genomes AF: 0.0468 AC: 7114 AN: 152078 Hom.: 187 Cov.: 31

Gnomad AFR AF: 0.0400

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.0504

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.0277

Gnomad SAS AF: 0.0655

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0522

Gnomad OTH AF: 0.0650

GnomAD4 exome AF: 0.0500 AC: 16688 AN: 333896 Hom.: 517 AF XY: 0.0507 AC XY: 9536 AN XY: 188190

African (AFR) AF: 0.0408 AC: 399 AN: 9780

American (AMR) AF: 0.0506 AC: 1403 AN: 27734

Ashkenazi Jewish (ASJ) AF: 0.0745 AC: 899 AN: 12060

East Asian (EAS) AF: 0.0235 AC: 276 AN: 11738

South Asian (SAS) AF: 0.0590 AC: 3512 AN: 59536

European-Finnish (FIN) AF: 0.0171 AC: 251 AN: 14712

Middle Eastern (MID) AF: 0.0487 AC: 128 AN: 2626

European-Non Finnish (NFE) AF: 0.0500 AC: 8961 AN: 179308

Other (OTH) AF: 0.0524 AC: 859 AN: 16402

GnomAD4 genome AF: 0.0468 AC: 7129 AN: 152196 Hom.: 188 Cov.: 31 AF XY: 0.0463 AC XY: 3443 AN XY: 74418

African (AFR) AF: 0.0404 AC: 1677 AN: 41530

American (AMR) AF: 0.0504 AC: 771 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 243 AN: 3470

East Asian (EAS) AF: 0.0278 AC: 144 AN: 5180

South Asian (SAS) AF: 0.0648 AC: 312 AN: 4818

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10604

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0521 AC: 3545 AN: 67988

Other (OTH) AF: 0.0643 AC: 136 AN: 2114

Alfa AF: 0.0497 Hom.: 625

Bravo AF: 0.0484

Asia WGS AF: 0.0440 AC: 154 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Susceptibility to severe coronavirus disease (COVID-19) (1)
-	1	-	Susceptibility to severe coronavirus disease (COVID-19) due to high plasma levels of TNF, TNFR, and/or TNFR5 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.84
PhyloP100		-0.40
PromoterAI		-0.036	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs361525; hg19: chr6-31543101;