6-31576412-A-G

Variant summary

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

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 frequency of 0.069 in 916,376 control chromosomes in the GnomAD database, including 2,659 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 0.072 ( 444 hom., cov: 31)
Exomes 𝑓: 0.068 ( 2215 hom. )

Consequence

TNF
NM_000594.4 intron

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.31
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]

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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=-0.85).
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.076 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNFNM_000594.4 linkc.187-122A>G intron_variant Intron 1 of 3 ENST00000449264.3 NP_000585.2 P01375Q5STB3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNFENST00000449264.3 linkc.187-122A>G intron_variant Intron 1 of 3 1 NM_000594.4 ENSP00000398698.2 P01375
TNFENST00000699334.1 linkc.187-355A>G intron_variant Intron 1 of 2 ENSP00000514308.1 A0A8V8TNL2

Frequencies

GnomAD3 genomes
AF:
0.0718
AC:
10920
AN:
152064
Hom.:
440
Cov.:
31
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
Gnomad4 AFR exome
AF:
0.0765
AC:
1443
AN:
18864
Gnomad4 AMR exome
AF:
0.0715
AC:
2133
AN:
29830
Gnomad4 ASJ exome
AF:
0.142
AC:
2370
AN:
16716
Gnomad4 EAS exome
AF:
0.0216
AC:
789
AN:
36510
Gnomad4 SAS exome
AF:
0.0729
AC:
4343
AN:
59614
Gnomad4 FIN exome
AF:
0.0209
AC:
904
AN:
43346
Gnomad4 NFE exome
AF:
0.0712
AC:
36969
AN:
519154
Gnomad4 Remaining exome
AF:
0.0791
AC:
2915
AN:
36850
Heterozygous variant carriers
0
2475
4950
7426
9901
12376
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Exome Het
Exome Hom
Variant carriers
0
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.:
31
AF XY:
0.0699
AC XY:
5200
AN XY:
74400
show subpopulations
Gnomad4 AFR
AF:
0.0783
AC:
0.0782598
AN:
0.0782598
Gnomad4 AMR
AF:
0.0739
AC:
0.0739239
AN:
0.0739239
Gnomad4 ASJ
AF:
0.138
AC:
0.138279
AN:
0.138279
Gnomad4 EAS
AF:
0.0284
AC:
0.0283893
AN:
0.0283893
Gnomad4 SAS
AF:
0.0770
AC:
0.076971
AN:
0.076971
Gnomad4 FIN
AF:
0.0153
AC:
0.0153397
AN:
0.0153397
Gnomad4 NFE
AF:
0.0734
AC:
0.0734118
AN:
0.0734118
Gnomad4 OTH
AF:
0.0946
AC:
0.0946074
AN:
0.0946074
Heterozygous variant carriers
0
509
1018
1528
2037
2546
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Genome Het
Genome Hom
Variant carriers
0
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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.85
CADD
Benign
0.44
DANN
Benign
0.67
Mutation Taster
=100/0
polymorphism (auto)

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs3093662; hg19: chr6-31544189; API