dbSNP rs3093662: TNF:c.187-122A>G (chr6-31576412-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is . The variant received -12 classification points (ACMG Germline Pathogenicity v2019): 0P and 12B. BA1BP4_Strong

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 cumulative frequency of 0.069 (AC=63,186) in the gnomAD database across 916,376 control chromosomes, including 2,659 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.104. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.31

Publications

177 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:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_000594.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript

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

BP4

Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Strong).

BA1

GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.1038 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000594.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNF	NM_000594.4	MANE Select	c.187-122A>G		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.187-122A>G		intron	N/A	ENSP00000398698.2	P01375
	TNF	ENST00000699334.1		c.187-355A>G		intron	N/A	ENSP00000514308.1	A0A8V8TNL2

Frequencies

GnomAD3 genomes

AF:

0.0718

AC:

10920

AN:

152064

Hom.:

440

Cov.:

show subpopulations

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

show subpopulations

African (AFR)

AF:

0.0765

AC:

1443

AN:

18864

American (AMR)

AF:

0.0715

AC:

2133

AN:

29830

Ashkenazi Jewish (ASJ)

AF:

0.142

AC:

2370

AN:

16716

East Asian (EAS)

AF:

0.0216

AC:

789

AN:

36510

South Asian (SAS)

AF:

0.0729

AC:

4343

AN:

59614

European-Finnish (FIN)

AF:

0.0209

AC:

904

AN:

43346

Middle Eastern (MID)

AF:

0.113

AC:

375

AN:

3310

European-Non Finnish (NFE)

AF:

0.0712

AC:

36969

AN:

519154

Other (OTH)

AF:

0.0791

AC:

2915

AN:

36850

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

2475

4950

7426

9901

12376

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

914

1828

2742

3656

4570

<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:

0.0719

AC:

10945

AN:

152182

Hom.:

444

Cov.:

AF XY:

0.0699

AC XY:

5200

AN XY:

74400

show subpopulations

African (AFR)

AF:

0.0783

AC:

3247

AN:

41490

American (AMR)

AF:

0.0739

AC:

1130

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.138

AC:

479

AN:

3464

East Asian (EAS)

AF:

0.0284

AC:

147

AN:

5178

South Asian (SAS)

AF:

0.0770

AC:

371

AN:

4820

European-Finnish (FIN)

AF:

0.0153

AC:

163

AN:

10626

Middle Eastern (MID)

AF:

0.158

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0734

AC:

4992

AN:

68000

Other (OTH)

AF:

0.0946

AC:

200

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

509

1018

1528

2037

2546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

122

244

366

488

610

<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:

0.0736

Hom.:

1883

Bravo

AF:

0.0767

Asia WGS

AF:

0.0580

AC:

202

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.0167

AC:

2019

AN:

120702

Turkish Variome

AF:

0.0783

AC:

121

AN:

1546

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.0212

AC:

190

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.101

AC:

236

AN:

2342

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.44

(source)

DANN

Benign

0.67

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

Local populations

ClinVar

Computational scores

Splicing

Publications

Other links and lift over