15-51094681-G-C

Variant names:

• chr15-51094681-G-C
• rs777218814
• ENST00000327536.5:c.179C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001311175.2(TNFAIP8L3):​c.-86C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000101 in 1,188,966 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 0.000014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: TNFAIP8L3 NM_001311175.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.965
• 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)

ENSG00000304751 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.057272643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNFAIP8L3	NM_001311175.2	c.-86C>G		5_prime_UTR_variant	Exon 1 of 2	ENST00000637513.2	NP_001298104.1
TNFAIP8L3	NM_207381.4	c.179C>G	p.Pro60Arg	missense_variant	Exon 2 of 3		NP_997264.2
MIR4713HG	NR_146310.1	n.194+57000G>C		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNFAIP8L3	ENST00000637513.2	c.-86C>G		5_prime_UTR_variant	Exon 1 of 2	1	NM_001311175.2	ENSP00000489743.1

Frequencies

GnomAD3 genomes AF: 0.0000137 AC: 2 AN: 146192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000136

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

GnomAD4 exome AF: 0.00000959 AC: 10 AN: 1042774 Hom.: 0 Cov.: 30 AF XY: 0.0000141 AC XY: 7 AN XY: 496816

African (AFR) AF: 0.00 AC: 0 AN: 20900

American (AMR) AF: 0.00 AC: 0 AN: 6620

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 11816

East Asian (EAS) AF: 0.00 AC: 0 AN: 22370

South Asian (SAS) AF: 0.000141 AC: 3 AN: 21220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2682

European-Non Finnish (NFE) AF: 0.00000334 AC: 3 AN: 898486

Other (OTH) AF: 0.0000998 AC: 4 AN: 40064

GnomAD4 genome AF: 0.0000137 AC: 2 AN: 146192 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71128

African (AFR) AF: 0.00 AC: 0 AN: 40814

American (AMR) AF: 0.000136 AC: 2 AN: 14720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3406

East Asian (EAS) AF: 0.00 AC: 0 AN: 4872

South Asian (SAS) AF: 0.00 AC: 0 AN: 4764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 308

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65784

Other (OTH) AF: 0.00 AC: 0 AN: 2012

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 11, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.179C>G (p.P60R) alteration is located in exon 2 (coding exon 2) of the TNFAIP8L3 gene. This alteration results from a C to G substitution at nucleotide position 179, causing the proline (P) at amino acid position 60 to be replaced by an arginine (R). 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	0.089
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	2.9
DANN	Benign	0.87
DEOGEN2	Benign	0.061	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.96
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.018
Sift	Benign	0.061	T
Sift4G	Benign	0.58	T
Polyphen		0.0	B
Vest4		0.12
MutPred		0.42		Gain of MoRF binding (P = 4e-04);
MVP		0.055
MPC		0.25
ClinPred		0.061	T
GERP RS		-6.0
PromoterAI		0.077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.038
gMVP		0.040
Mutation Taster		=99/1	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: rs777218814; hg19: chr15-51386878;