15-51058113-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001311175.2(TNFAIP8L3):​c.383C>T​(p.Thr128Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000489 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000053 ( 0 hom. )

Consequence

TNFAIP8L3
NM_001311175.2 missense

Scores

12
3
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.91

Publications

1 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)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TNFAIP8L3NM_001311175.2 linkc.383C>T p.Thr128Ile missense_variant Exon 2 of 2 ENST00000637513.2 NP_001298104.1 Q5GJ75A0A1B0GTK8
TNFAIP8L3NM_207381.4 linkc.647C>T p.Thr216Ile missense_variant Exon 3 of 3 NP_997264.2 Q5GJ75
MIR4713HGNR_146310.1 linkn.194+20432G>A intron_variant Intron 1 of 2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNFAIP8L3ENST00000637513.2 linkc.383C>T p.Thr128Ile missense_variant Exon 2 of 2 1 NM_001311175.2 ENSP00000489743.1 A0A1B0GTK8

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000943
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.0000995
AC:
25
AN:
251184
AF XY:
0.0000810
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000462
Gnomad NFE exome
AF:
0.000203
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000527
AC:
77
AN:
1461858
Hom.:
0
Cov.:
31
AF XY:
0.0000481
AC XY:
35
AN XY:
727226
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26134
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39698
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
0.000112
AC:
6
AN:
53418
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.0000585
AC:
65
AN:
1111992
Other (OTH)
AF:
0.0000993
AC:
6
AN:
60396
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.483
Heterozygous variant carriers
0
5
10
14
19
24
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:
0.0000131
AC:
2
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74352
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41462
American (AMR)
AF:
0.00
AC:
0
AN:
15274
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.0000943
AC:
1
AN:
10610
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.0000147
AC:
1
AN:
68042
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
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:
0.0000847
Hom.:
0
Bravo
AF:
0.0000340
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1
ExAC
AF:
0.000165
AC:
20
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 12, 2024
Ambry Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

The c.647C>T (p.T216I) alteration is located in exon 3 (coding exon 3) of the TNFAIP8L3 gene. This alteration results from a C to T substitution at nucleotide position 647, causing the threonine (T) at amino acid position 216 to be replaced by an isoleucine (I). 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
Pathogenic
0.98
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Pathogenic
0.21
CADD
Uncertain
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.35
T;.
Eigen
Pathogenic
0.89
Eigen_PC
Pathogenic
0.84
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.037
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Benign
-0.41
T
MutationAssessor
Pathogenic
3.1
M;.
PhyloP100
9.9
PrimateAI
Uncertain
0.71
T
PROVEAN
Pathogenic
-5.7
D;.
REVEL
Pathogenic
0.73
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0010
D;.
Polyphen
1.0
D;.
Vest4
0.92
MVP
0.56
MPC
0.83
ClinPred
0.67
D
GERP RS
5.5
Varity_R
0.86
gMVP
0.72
Mutation Taster
=13/87
disease causing

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: rs377692647; hg19: chr15-51350310; API