11-126292712-G-T

Position:

• chr11-126292712-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001318777.2(TIRAP):​c.303G>T​(p.Gln101His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TIRAP NM_001318777.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.04

Genes affected

TIRAP (HGNC:17192): (TIR domain containing adaptor protein) The innate immune system recognizes microbial pathogens through Toll-like receptors (TLRs), which identify pathogen-associated molecular patterns. Different TLRs recognize different pathogen-associated molecular patterns and all TLRs have a Toll-interleukin 1 receptor (TIR) domain, which is responsible for signal transduction. The protein encoded by this gene is a TIR adaptor protein involved in the TLR4 signaling pathway of the immune system. It activates NF-kappa-B, MAPK1, MAPK3 and JNK, which then results in cytokine secretion and the inflammatory response. Alternative splicing of this gene results in several transcript variants; however, not all variants have been fully described. [provided by RefSeq, Jul 2008]

TIRAP (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.39070284).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.303G>T	p.Gln101His	missense_variant	4/5	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.303G>T	p.Gln101His	missense_variant	4/4		NP_001305705.1
TIRAP	NM_148910.3	c.303G>T	p.Gln101His	missense_variant	5/5		NP_683708.1
TIRAP	NM_001039661.2	c.303G>T	p.Gln101His	missense_variant	5/6		NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.303G>T	p.Gln101His	missense_variant	4/5	2	NM_001318777.2	ENSP00000376446.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Benign	0.95
DEOGEN2	Benign	0.077	T;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.016
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.71	.;T;.
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.1	M;M;M
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.035
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.19	T;T;T
Polyphen		0.20	B;.;B
Vest4		0.22
MutPred		0.37		Gain of catalytic residue at D102 (P = 0.0896);Gain of catalytic residue at D102 (P = 0.0896);Gain of catalytic residue at D102 (P = 0.0896);
MVP		0.45
MPC		0.050
ClinPred		0.63	D
GERP RS		4.4
Varity_R		0.42
gMVP		0.29

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: rs3802814; hg19: chr11-126162607;