rs1800610

Positions:

• chr6-31576050-G-A

Variant summary

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

The NM_000594.4(TNF):​c.186+123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0842 in 1,037,560 control chromosomes in the GnomAD database, including 5,008 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 0.087 (834 hom., cov: 31)
  • Exomes 𝑓: 0.084 (4174 hom.)
• Consequence: TNF NM_000594.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.61

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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.166 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNF	NM_000594.4	c.186+123G>A		intron_variant		ENST00000449264.3	NP_000585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNF	ENST00000449264.3	c.186+123G>A		intron_variant		1	NM_000594.4	ENSP00000398698	P1
TNF	ENST00000699334.1	c.186+123G>A		intron_variant				ENSP00000514308

Frequencies

GnomAD3 genomes AF: 0.0872 AC: 13263 AN: 152026 Hom.: 831 Cov.: 31

Gnomad AFR AF: 0.0301

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.255

Gnomad EAS AF: 0.149

Gnomad SAS AF: 0.124

Gnomad FIN AF: 0.0553

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0919

Gnomad OTH AF: 0.0948

GnomAD4 exome AF: 0.0836 AC: 74061 AN: 885416 Hom.: 4174 AF XY: 0.0863 AC XY: 37406 AN XY: 433550

Gnomad4 AFR exome AF: 0.0304

Gnomad4 AMR exome AF: 0.189

Gnomad4 ASJ exome AF: 0.230

Gnomad4 EAS exome AF: 0.200

Gnomad4 SAS exome AF: 0.116

Gnomad4 FIN exome AF: 0.0520

Gnomad4 NFE exome AF: 0.0745

Gnomad4 OTH exome AF: 0.0930

GnomAD4 genome AF: 0.0873 AC: 13286 AN: 152144 Hom.: 834 Cov.: 31 AF XY: 0.0894 AC XY: 6647 AN XY: 74368

Gnomad4 AFR AF: 0.0301

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.255

Gnomad4 EAS AF: 0.149

Gnomad4 SAS AF: 0.124

Gnomad4 FIN AF: 0.0553

Gnomad4 NFE AF: 0.0919

Gnomad4 OTH AF: 0.0995

Alfa AF: 0.0875 Hom.: 157

Bravo AF: 0.0929

Asia WGS AF: 0.123 AC: 427 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.60
DANN	Benign	0.77

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: rs1800610; hg19: chr6-31543827;