rs41297589

Variant names:

• chr6-31575485-T-A
• rs41297589
• NM_000594.4:c.-257T>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000594.4(TNF):​c.-257T>A variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00765 in 538,866 control chromosomes in the GnomAD database, including 232 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 0.0032 (17 hom., cov: 31)
  • Exomes 𝑓: 0.0094 (215 hom.)
• Consequence: TNF NM_000594.4 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.42

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.059 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNF	NM_000594.4	c.-257T>A		upstream_gene_variant		ENST00000449264.3	NP_000585.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNF	ENST00000449264.3	c.-257T>A		upstream_gene_variant		1	NM_000594.4	ENSP00000398698.2

Frequencies

GnomAD3 genomes AF: 0.00316 AC: 481 AN: 152046 Hom.: 18 Cov.: 31

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000577

Gnomad EAS AF: 0.00483

Gnomad SAS AF: 0.0645

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00141

Gnomad OTH AF: 0.00383

GnomAD4 exome AF: 0.00942 AC: 3642 AN: 386702 Hom.: 215 AF XY: 0.0141 AC XY: 2856 AN XY: 203072

Gnomad4 AFR exome AF: 0.000282

Gnomad4 AMR exome AF: 0.000748

Gnomad4 ASJ exome AF: 0.000809

Gnomad4 EAS exome AF: 0.00133

Gnomad4 SAS exome AF: 0.0873

Gnomad4 FIN exome AF: 0.000147

Gnomad4 NFE exome AF: 0.00159

Gnomad4 OTH exome AF: 0.00385

GnomAD4 genome AF: 0.00315 AC: 480 AN: 152164 Hom.: 17 Cov.: 31 AF XY: 0.00425 AC XY: 316 AN XY: 74384

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000577

Gnomad4 EAS AF: 0.00465

Gnomad4 SAS AF: 0.0649

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00141

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00164 Hom.: 1

Bravo AF: 0.00142

Asia WGS AF: 0.0140 AC: 50 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Benign	0.91

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs41297589; hg19: chr6-31543262;