NM_001318777.2:c.25G>A

Variant names:

• chr11-126290919-G-A
• rs8177369
• NM_001318777.2:c.25G>A

Variant summary

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

The NM_001318777.2(TIRAP):​c.25G>A​(p.Ala9Thr) 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. 15/22 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: 1.11
• Publications: 9 publications found

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]

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=0.06378561).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318777.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIRAP	NM_001318777.2	MANE Select	c.25G>A	p.Ala9Thr	missense	Exon 3 of 5	NP_001305706.1
	TIRAP	NM_001318776.2		c.25G>A	p.Ala9Thr	missense	Exon 3 of 4	NP_001305705.1
	TIRAP	NM_148910.3		c.25G>A	p.Ala9Thr	missense	Exon 4 of 5	NP_683708.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIRAP	ENST00000392679.6	TSL:2 MANE Select	c.25G>A	p.Ala9Thr	missense	Exon 3 of 5	ENSP00000376446.1
	TIRAP	ENST00000392678.7	TSL:1	c.25G>A	p.Ala9Thr	missense	Exon 4 of 5	ENSP00000376445.3
	TIRAP	ENST00000392680.6	TSL:1	c.25G>A	p.Ala9Thr	missense	Exon 4 of 6	ENSP00000376447.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.083	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.61	T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.064	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.1
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.60	N
REVEL	Benign	0.041
Sift	Benign	0.091	T
Sift4G	Benign	0.14	T
Polyphen		0.0060	B
Vest4		0.070
MutPred		0.14		Gain of phosphorylation at A9 (P = 0.0017)
MVP		0.43
MPC		0.028
ClinPred		0.10	T
GERP RS		3.1
Varity_R		0.036
gMVP		0.30
Mutation Taster		=98/2	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: rs8177369; hg19: chr11-126160814;