15-51094562-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001311175.2(TNFAIP8L3):​c.34G>A​(p.Glu12Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000002 in 1,502,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

TNFAIP8L3
NM_001311175.2 missense

Scores

1
3
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.54

Publications

0 publications found
Variant links:
Genes affected
TNFAIP8L3 (HGNC:20620): (TNF alpha induced protein 8 like 3) Predicted to enable phosphatidylinositol binding activity and phosphatidylinositol transfer activity. Predicted to be involved in several processes, including inositol lipid-mediated signaling; positive regulation of intracellular signal transduction; and positive regulation of phosphatidylinositol 3-kinase activity. Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]
MIR4713HG (HGNC:53124): (MIR4713 host gene)

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20015788).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNFAIP8L3NM_001311175.2 linkc.34G>A p.Glu12Lys missense_variant Exon 1 of 2 ENST00000637513.2 NP_001298104.1 Q5GJ75A0A1B0GTK8
TNFAIP8L3NM_207381.4 linkc.298G>A p.Glu100Lys missense_variant Exon 2 of 3 NP_997264.2 Q5GJ75
MIR4713HGNR_146310.1 linkn.194+56881C>T intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNFAIP8L3ENST00000637513.2 linkc.34G>A p.Glu12Lys missense_variant Exon 1 of 2 1 NM_001311175.2 ENSP00000489743.1 A0A1B0GTK8

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152122
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000148
AC:
2
AN:
1350204
Hom.:
0
Cov.:
30
AF XY:
0.00000150
AC XY:
1
AN XY:
667044
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
27680
American (AMR)
AF:
0.00
AC:
0
AN:
33618
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23888
East Asian (EAS)
AF:
0.00
AC:
0
AN:
29656
South Asian (SAS)
AF:
0.0000260
AC:
2
AN:
76778
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
34742
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5348
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1062470
Other (OTH)
AF:
0.00
AC:
0
AN:
56024
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.650
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.00000657
AC:
1
AN:
152122
Hom.:
0
Cov.:
33
AF XY:
0.0000135
AC XY:
1
AN XY:
74310
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41448
American (AMR)
AF:
0.0000654
AC:
1
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4836
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10596
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67992
Other (OTH)
AF:
0.00
AC:
0
AN:
2090
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 09, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.298G>A (p.E100K) alteration is located in exon 2 (coding exon 2) of the TNFAIP8L3 gene. This alteration results from a G to A substitution at nucleotide position 298, causing the glutamic acid (E) at amino acid position 100 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.27
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.090
T;.
Eigen
Benign
0.13
Eigen_PC
Benign
0.10
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.77
T;T
M_CAP
Benign
0.059
D
MetaRNN
Benign
0.20
T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N;.
PhyloP100
2.5
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-1.1
N;.
REVEL
Benign
0.12
Sift
Benign
0.054
T;.
Sift4G
Uncertain
0.023
D;.
Polyphen
1.0
D;.
Vest4
0.24
MutPred
0.13
Gain of ubiquitination at E100 (P = 4e-04);.;
MVP
0.11
MPC
0.26
ClinPred
0.68
D
GERP RS
3.8
PromoterAI
0.056
Neutral
Varity_R
0.19
gMVP
0.17
Mutation Taster
=80/20
polymorphism

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

Other links and lift over

dbSNP: rs867642638; hg19: chr15-51386759; API