NM_000594.4:c.186+123G>A

Variant names:

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.186+123G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.0842 (AC=87,347) in the gnomAD database across 1,037,560 control chromosomes, including 5,008 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.196. 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 0.087 ( 834 hom., cov: 31)

Exomes 𝑓: 0.084 ( 4174 hom. )

Consequence

TNF
NM_000594.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.61

Publications

116 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 = 0.1961 — 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.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.:

show subpopulations

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

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

3431

6863

10294

13726

17157

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1882

3764

5646

7528

9410

<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:

0.0873

AC:

13286

AN:

152144

Hom.:

834

Cov.:

AF XY:

0.0894

AC XY:

6647

AN XY:

74368

show subpopulations

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0919

AC:

6247

AN:

67998

Other (OTH)

AF:

0.0995

AC:

210

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

594

1189

1783

2378

2972

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<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:

0.0948

Hom.:

1613

Bravo

AF:

0.0929

Asia WGS

AF:

0.123

AC:

427

AN:

3478

Local populations

ToMMo 61KJPN (+60KJPN MNV)

AF:

0.217

AC:

26006

AN:

119980

Turkish Variome

AF:

0.203

AC:

314

AN:

1544

Hom.:

WBBC (Westlake BioBank for Chinese) pilot

AF:

0.135

AC:

1208

AN:

8960

Hom.:

ABraOM SABE-WGS-1171

AF:

0.112

AC:

262

AN:

2342

Hom.:

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

(source)

DANN

Benign

0.77

PhyloP100

-1.6

PromoterAI

-0.031

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

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