Genetic Variant TNF:c.186+54G>A (chr6-31575981-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000594.4(TNF):c.186+54G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0391 in 1,423,414 control chromosomes in the GnomAD database, including 1,262 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 0.036 ( 104 hom., cov: 31)

Exomes 𝑓: 0.039 ( 1158 hom. )

Consequence

TNF
NM_000594.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.482

Publications

55 publications found

Variant links:

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]

TNF links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0562 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+54G>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+54G>A		intron	N/A	ENSP00000398698.2	P01375
	TNF	ENST00000699334.1		c.186+54G>A		intron	N/A	ENSP00000514308.1	A0A8V8TNL2

Frequencies

GnomAD3 genomes

AF:

0.0358

AC:

5442

AN:

152106

Hom.:

101

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0316

Gnomad AMI

AF:

0.153

Gnomad AMR

AF:

0.0341

Gnomad ASJ

AF:

0.0473

Gnomad EAS

AF:

0.0276

Gnomad SAS

AF:

0.0628

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.0316

Gnomad NFE

AF:

0.0388

Gnomad OTH

AF:

0.0407

GnomAD4 exome

AF:

0.0395

AC:

50163

AN:

1271190

Hom.:

1158

AF XY:

0.0396

AC XY:

24600

AN XY:

620858

show subpopulations

African (AFR)

AF:

0.0291

AC:

779

AN:

26734

American (AMR)

AF:

0.0325

AC:

764

AN:

23498

Ashkenazi Jewish (ASJ)

AF:

0.0487

AC:

861

AN:

17682

East Asian (EAS)

AF:

0.0208

AC:

688

AN:

33086

South Asian (SAS)

AF:

0.0572

AC:

3281

AN:

57380

European-Finnish (FIN)

AF:

0.0144

AC:

661

AN:

45872

Middle Eastern (MID)

AF:

0.0310

AC:

147

AN:

4744

European-Non Finnish (NFE)

AF:

0.0404

AC:

40822

AN:

1010858

Other (OTH)

AF:

0.0421

AC:

2160

AN:

51336

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

2466

4931

7397

9862

12328

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1708

3416

5124

6832

8540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0359

AC:

5460

AN:

152224

Hom.:

104

Cov.:

AF XY:

0.0357

AC XY:

2661

AN XY:

74438

show subpopulations

African (AFR)

AF:

0.0320

AC:

1328

AN:

41512

American (AMR)

AF:

0.0342

AC:

523

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0473

AC:

164

AN:

3470

East Asian (EAS)

AF:

0.0276

AC:

143

AN:

5178

South Asian (SAS)

AF:

0.0620

AC:

299

AN:

4822

European-Finnish (FIN)

AF:

0.0122

AC:

130

AN:

10620

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0388

AC:

2639

AN:

68020

Other (OTH)

AF:

0.0403

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

271

543

814

1086

1357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

198

264

330

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0341

Hom.:

267

Bravo

AF:

0.0365

Asia WGS

AF:

0.0420

AC:

147

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.4

(source)

DANN

Benign

0.44

PhyloP100

-0.48

PromoterAI

-0.080

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over