Genetic Variant TNFAIP8L3:p.Tyr123Cys (chr15-51058128-T-C) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001311175.2(TNFAIP8L3):c.368A>G(p.Tyr123Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000204 in 1,614,254 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

TNFAIP8L3
NM_001311175.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.21

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]

TNFAIP8L3 links:

MIR4713HG (HGNC:53124): (MIR4713 host gene)

MIR4713HG links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFAIP8L3	NM_001311175.2 link	c.368A>G	p.Tyr123Cys	missense_variant	Exon 2 of 2	ENST00000637513.2	NP_001298104.1	Q5GJ75A0A1B0GTK8
TNFAIP8L3	NM_207381.4 link	c.632A>G	p.Tyr211Cys	missense_variant	Exon 3 of 3		NP_997264.2	Q5GJ75
MIR4713HG	NR_146310.1 link	n.194+20447T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TNFAIP8L3	ENST00000637513.2 link	c.368A>G	p.Tyr123Cys	missense_variant	Exon 2 of 2	1	NM_001311175.2	ENSP00000489743.1	A0A1B0GTK8
TNFAIP8L3	ENST00000327536.5 link	c.632A>G	p.Tyr211Cys	missense_variant	Exon 3 of 3	1		ENSP00000328016.5	Q5GJ75
TNFAIP8L3	ENST00000649177.1 link	c.230A>G	p.Tyr77Cys	missense_variant	Exon 2 of 2			ENSP00000498365.1	A0A494C051
MIR4713HG	ENST00000559909.1 link	n.194+20447T>C		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

152242

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251250

Hom.:

AF XY:

0.0000295

AC XY:

AN XY:

135792

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000116

AC:

AN:

1461894

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.000105

AC:

AN:

152360

Hom.:

Cov.:

AF XY:

0.0000939

AC XY:

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000164

Hom.:

Bravo

AF:

0.0000831

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.632A>G (p.Y211C) alteration is located in exon 3 (coding exon 3) of the TNFAIP8L3 gene. This alteration results from a A to G substitution at nucleotide position 632, causing the tyrosine (Y) at amino acid position 211 to be replaced by a cysteine (C). 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

0.22

BayesDel_addAF

Benign

-0.0096

BayesDel_noAF

Uncertain

0.10

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.88

D;D

M_CAP

Benign

0.036

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Benign

-0.71

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Pathogenic

0.79

PROVEAN

Pathogenic

-6.7

D;.

REVEL

Uncertain

0.56

Sift

Benign

0.043

D;.

Sift4G

Uncertain

0.0050

D;.

Polyphen

1.0

D;.

Vest4

0.57

MVP

0.47

MPC

0.92

ClinPred

0.35

GERP RS

5.5

Varity_R

0.78

gMVP

0.54

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

LitVar

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over