rs2065216465

Variant names:

• chr15-51057918-T-C
• rs2065216465
• NM_001311175.2:c.578A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001311175.2(TNFAIP8L3):​c.578A>G​(p.Glu193Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000376 in 1,596,570 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TNFAIP8L3 NM_001311175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96
• Publications: 0 publications found

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)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36619467).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFAIP8L3	NM_001311175.2	c.578A>G	p.Glu193Gly	missense_variant	Exon 2 of 2	ENST00000637513.2	NP_001298104.1
TNFAIP8L3	NM_207381.4	c.842A>G	p.Glu281Gly	missense_variant	Exon 3 of 3		NP_997264.2
MIR4713HG	NR_146310.1	n.194+20237T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFAIP8L3	ENST00000637513.2	c.578A>G	p.Glu193Gly	missense_variant	Exon 2 of 2	1	NM_001311175.2	ENSP00000489743.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000346 AC: 5 AN: 1444362 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 717464

African (AFR) AF: 0.00 AC: 0 AN: 32700

American (AMR) AF: 0.00 AC: 0 AN: 40694

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39542

South Asian (SAS) AF: 0.00 AC: 0 AN: 83020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53102

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.00000453 AC: 5 AN: 1104918

Other (OTH) AF: 0.00 AC: 0 AN: 59632

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74362

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.00 AC: 0 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2092

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.842A>G (p.E281G) 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 842, causing the glutamic acid (E) at amino acid position 281 to be replaced by a glycine (G). 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	0.21
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	0.011
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.85	T;T
M_CAP	Benign	0.0036	T
MetaRNN	Benign	0.37	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.
PhyloP100		4.0
PrimateAI	Benign	0.38	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Benign	0.082
Sift	Benign	0.10	T;.
Sift4G	Benign	0.12	T;.
Polyphen		0.012	B;.
Vest4		0.14
MutPred		0.46		Loss of ubiquitination at K285 (P = 0.046);.;
MVP		0.35
MPC		0.26
ClinPred		0.79	D
GERP RS		5.8
Varity_R		0.27
gMVP		0.28
Mutation Taster		=55/45	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

Other links and lift over

dbSNP: rs2065216465; hg19: chr15-51350115;