6-31576412-A-G

Position:

• chr6-31576412-A-G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.076 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TNF	NM_000594.4	c.187-122A>G		intron_variant		ENST00000449264.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNF	ENST00000449264.3	c.187-122A>G		intron_variant		1	NM_000594.4	P1
TNF	ENST00000699334.1	c.187-355A>G		intron_variant

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

Gnomad4 AFR exome AF: 0.0765

Gnomad4 AMR exome AF: 0.0715

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.0216

Gnomad4 SAS exome AF: 0.0729

Gnomad4 FIN exome AF: 0.0209

Gnomad4 NFE exome AF: 0.0712

Gnomad4 OTH exome AF: 0.0791

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

Gnomad4 AFR AF: 0.0783

Gnomad4 AMR AF: 0.0739

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.0284

Gnomad4 SAS AF: 0.0770

Gnomad4 FIN AF: 0.0153

Gnomad4 NFE AF: 0.0734

Gnomad4 OTH AF: 0.0946

Alfa AF: 0.0780 Hom.: 968

Bravo AF: 0.0767

Asia WGS AF: 0.0580 AC: 202 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.44
DANN	Benign	0.67

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

Publications

LitVar

Other links and lift over

dbSNP: rs3093662; hg19: chr6-31544189;