chr6-31576050-G-A

Variant names:

• chr6-31576050-G-A
• rs1800610
• NM_000594.4:c.186+123G>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.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
• Publications: 114 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.166 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNF	NM_000594.4	MANE Select	c.186+123G>A		intron	N/A	NP_000585.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNF	ENST00000449264.3	TSL:1 MANE Select	c.186+123G>A		intron	N/A	ENSP00000398698.2	P01375
	TNF	ENST00000699334.1		c.186+123G>A		intron	N/A	ENSP00000514308.1	A0A8V8TNL2

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

African (AFR) AF: 0.0304 AC: 578 AN: 19018

American (AMR) AF: 0.189 AC: 2361 AN: 12488

Ashkenazi Jewish (ASJ) AF: 0.230 AC: 3290 AN: 14294

East Asian (EAS) AF: 0.200 AC: 5588 AN: 27874

South Asian (SAS) AF: 0.116 AC: 4242 AN: 36672

European-Finnish (FIN) AF: 0.0520 AC: 1541 AN: 29634

Middle Eastern (MID) AF: 0.142 AC: 387 AN: 2718

European-Non Finnish (NFE) AF: 0.0745 AC: 52475 AN: 704038

Other (OTH) AF: 0.0930 AC: 3599 AN: 38680

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

African (AFR) AF: 0.0301 AC: 1250 AN: 41534

American (AMR) AF: 0.172 AC: 2621 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.255 AC: 886 AN: 3470

East Asian (EAS) AF: 0.149 AC: 769 AN: 5166

South Asian (SAS) AF: 0.124 AC: 598 AN: 4814

European-Finnish (FIN) AF: 0.0553 AC: 585 AN: 10588

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.0919 AC: 6247 AN: 67998

Other (OTH) AF: 0.0995 AC: 210 AN: 2110

Alfa AF: 0.0948 Hom.: 1613

Bravo AF: 0.0929

Asia WGS AF: 0.123 AC: 427 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.60
DANN	Benign	0.77
PhyloP100		-1.6
PromoterAI		-0.031	Neutral
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: rs1800610; hg19: chr6-31543827;