Genetic Variant TNFAIP8L3:p.Ala58Pro (chr15-51105005-C-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_207381.4(TNFAIP8L3):c.172G>C(p.Ala58Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00605 in 1,614,156 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 3 hom., cov: 32)

Exomes 𝑓: 0.0062 ( 37 hom. )

Consequence

TNFAIP8L3
NM_207381.4 missense, splice_region

Scores

Splicing: ADA: 1.000

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0760

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 Benign. Variant got -12 ACMG points.

BP6

Variant 15-51105005-C-G is Benign according to our data. Variant chr15-51105005-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 719370.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFAIP8L3	NM_207381.4 link	c.172G>C	p.Ala58Pro	missense_variant, splice_region_variant	Exon 1 of 3		NP_997264.2	Q5GJ75
MIR4713HG	NR_146310.1 link	n.194+67324C>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFAIP8L3	ENST00000327536.5 link	c.172G>C	p.Ala58Pro	missense_variant, splice_region_variant	Exon 1 of 3	1		ENSP00000328016.5		Q5GJ75
MIR4713HG	ENST00000559909.1 link	n.194+67324C>G		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes

AF:

0.00416

AC:

633

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00741

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00344

AC:

862

AN:

250752

Hom.:

AF XY:

0.00350

AC XY:

474

AN XY:

135616

show subpopulations

Gnomad AFR exome

AF:

0.00105

Gnomad AMR exome

AF:

0.000809

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000719

Gnomad FIN exome

AF:

0.00379

Gnomad NFE exome

AF:

0.00608

Gnomad OTH exome

AF:

0.00261

GnomAD4 exome

AF:

0.00625

AC:

9136

AN:

1461842

Hom.:

Cov.:

AF XY:

0.00604

AC XY:

4393

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000896

Gnomad4 AMR exome

AF:

0.000850

Gnomad4 ASJ exome

AF:

0.00122

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000754

Gnomad4 FIN exome

AF:

0.00464

Gnomad4 NFE exome

AF:

0.00764

Gnomad4 OTH exome

AF:

0.00366

GnomAD4 genome

AF:

0.00416

AC:

633

AN:

152314

Hom.:

Cov.:

AF XY:

0.00381

AC XY:

284

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.00203

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00367

Gnomad4 NFE

AF:

0.00741

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00568

Hom.:

Bravo

AF:

0.00381

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.00228

AC:

ESP6500EA

AF:

0.00815

AC:

ExAC

AF:

0.00324

AC:

393

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00545

EpiControl

AF:

0.00456

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Apr 10, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.052

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.91

FATHMM_MKL

Benign

0.032

LIST_S2

Benign

0.26

M_CAP

Benign

0.010

MetaRNN

Benign

0.0033

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.43

PROVEAN

Benign

0.27

REVEL

Benign

0.0070

Sift

Benign

0.062

Sift4G

Benign

0.12

Polyphen

0.49

Vest4

0.23

MVP

0.17

MPC

0.31

ClinPred

0.0074

GERP RS

1.7

Varity_R

0.11

gMVP

0.055

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.050

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