15-51058015-T-C

Variant names:

• chr15-51058015-T-C
• rs1342790806
• NM_001311175.2:c.481A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001311175.2(TNFAIP8L3):​c.481A>G​(p.Ile161Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,886 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TNFAIP8L3 NM_001311175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.20

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFAIP8L3	NM_001311175.2	c.481A>G	p.Ile161Val	missense_variant	Exon 2 of 2	ENST00000637513.2	NP_001298104.1
TNFAIP8L3	NM_207381.4	c.745A>G	p.Ile249Val	missense_variant	Exon 3 of 3		NP_997264.2
MIR4713HG	NR_146310.1	n.194+20334T>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFAIP8L3	ENST00000637513.2	c.481A>G	p.Ile161Val	missense_variant	Exon 2 of 2	1	NM_001311175.2	ENSP00000489743.1
TNFAIP8L3	ENST00000327536.5	c.745A>G	p.Ile249Val	missense_variant	Exon 3 of 3	1		ENSP00000328016.5
TNFAIP8L3	ENST00000649177.1	c.343A>G	p.Ile115Val	missense_variant	Exon 2 of 2			ENSP00000498365.1
MIR4713HG	ENST00000559909.1	n.194+20334T>C		intron_variant	Intron 1 of 2	4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251358 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135846

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461886 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.745A>G (p.I249V) 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 745, causing the isoleucine (I) at amino acid position 249 to be replaced by a valine (V). 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	0.28
BayesDel_addAF	Benign	-0.043	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.012	T
MetaRNN	Pathogenic	0.76	D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.42	N;.
REVEL	Benign	0.24
Sift	Benign	0.31	T;.
Sift4G	Benign	0.22	T;.
Polyphen		0.98	D;.
Vest4		0.28
MutPred		0.82		Gain of methylation at R248 (P = 0.0519);.;
MVP		0.39
MPC		0.74
ClinPred		0.61	D
GERP RS		5.6
Varity_R		0.16
gMVP		0.36

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

Other links and lift over

dbSNP: rs1342790806; hg19: chr15-51350212;