dbSNP rs3093665: TNF:c.*77A>C (chr6-31577614-A-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_000594.4(TNF):c.*77A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0206 in 1,563,882 control chromosomes in the GnomAD database, including 472 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 0.025 ( 56 hom., cov: 32)

Exomes 𝑓: 0.020 ( 416 hom. )

Consequence

TNF
NM_000594.4 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.325

Publications

38 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=-0.78).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0245 (3738/152280) while in subpopulation AFR AF = 0.0359 (1493/41546). AF 95% confidence interval is 0.0344. There are 56 homozygotes in GnomAd4. There are 1723 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 3738 AD gene.

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.*77A>C		3_prime_UTR	Exon 4 of 4	NP_000585.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNF	ENST00000449264.3	TSL:1 MANE Select	c.*77A>C		3_prime_UTR	Exon 4 of 4	ENSP00000398698.2	P01375
	TNF	ENST00000699334.1		c.*511A>C		downstream_gene	N/A	ENSP00000514308.1	A0A8V8TNL2

Frequencies

GnomAD3 genomes

AF:

0.0245

AC:

3731

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0359

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0236

Gnomad ASJ

AF:

0.0688

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0212

Gnomad OTH

AF:

0.0296

GnomAD2 exomes

AF:

0.0193

AC:

4245

AN:

219800

AF XY:

0.0197

show subpopulations

Gnomad AFR exome

AF:

0.0369

Gnomad AMR exome

AF:

0.0194

Gnomad ASJ exome

AF:

0.0680

Gnomad EAS exome

AF:

0.000238

Gnomad FIN exome

AF:

0.00205

Gnomad NFE exome

AF:

0.0210

Gnomad OTH exome

AF:

0.0242

GnomAD4 exome

AF:

0.0201

AC:

28406

AN:

1411602

Hom.:

416

Cov.:

AF XY:

0.0203

AC XY:

14251

AN XY:

702078

show subpopulations

African (AFR)

AF:

0.0359

AC:

1172

AN:

32678

American (AMR)

AF:

0.0210

AC:

886

AN:

42126

Ashkenazi Jewish (ASJ)

AF:

0.0701

AC:

1793

AN:

25570

East Asian (EAS)

AF:

0.000204

AC:

AN:

39188

South Asian (SAS)

AF:

0.0108

AC:

909

AN:

84272

European-Finnish (FIN)

AF:

0.00271

AC:

133

AN:

49050

Middle Eastern (MID)

AF:

0.0516

AC:

293

AN:

5682

European-Non Finnish (NFE)

AF:

0.0200

AC:

21513

AN:

1074270

Other (OTH)

AF:

0.0289

AC:

1699

AN:

58766

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1481

2962

4444

5925

7406

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

838

1676

2514

3352

4190

<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:

0.0245

AC:

3738

AN:

152280

Hom.:

Cov.:

AF XY:

0.0231

AC XY:

1723

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0359

AC:

1493

AN:

41546

American (AMR)

AF:

0.0235

AC:

360

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0688

AC:

239

AN:

3472

East Asian (EAS)

AF:

0.000385

AC:

AN:

5192

South Asian (SAS)

AF:

0.0122

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00179

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0986

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0212

AC:

1445

AN:

68008

Other (OTH)

AF:

0.0293

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

191

382

573

764

955

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

160

200

<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:

0.0235

Hom.:

220

Bravo

AF:

0.0275

Asia WGS

AF:

0.0140

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

1.5

(source)

DANN

Benign

0.72

PhyloP100

-0.33

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