chr11-126292695-G-T

Position:

• chr11-126292695-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001318777.2(TIRAP):​c.286G>T​(p.Asp96Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,461,528 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D96N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: TIRAP NM_001318777.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.55

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.286G>T	p.Asp96Tyr	missense_variant	4/5	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.286G>T	p.Asp96Tyr	missense_variant	4/4		NP_001305705.1
TIRAP	NM_148910.3	c.286G>T	p.Asp96Tyr	missense_variant	5/5		NP_683708.1
TIRAP	NM_001039661.2	c.286G>T	p.Asp96Tyr	missense_variant	5/6		NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.286G>T	p.Asp96Tyr	missense_variant	4/5	2	NM_001318777.2	ENSP00000376446.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 250018 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135254

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000580

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: 0.00000885

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000547 AC: 8 AN: 1461528 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727034

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000448

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: 0.00000540

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.44	T;.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.84	.;T;.
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.94	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-8.4	D;D;D
REVEL	Uncertain	0.56
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.95
MutPred		0.76		Loss of disorder (P = 0.0509);Loss of disorder (P = 0.0509);Loss of disorder (P = 0.0509);
MVP		0.63
MPC		0.24
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.99
gMVP		0.91

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: rs8177400; hg19: chr11-126162590;