11-126290931-C-T

Position:

• chr11-126290931-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001318777.2(TIRAP):​c.37C>T​(p.Arg13Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,606,976 control chromosomes in the GnomAD database, including 316 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.015 (23 hom., cov: 32)
  • Exomes 𝑓: 0.019 (293 hom.)
• Consequence: TIRAP NM_001318777.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0780

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0018643737).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0148 (2258/152280) while in subpopulation NFE AF= 0.0213 (1448/68032). AF 95% confidence interval is 0.0204. There are 23 homozygotes in gnomad4. There are 1079 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.37C>T	p.Arg13Trp	missense_variant	3/5	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.37C>T	p.Arg13Trp	missense_variant	3/4		NP_001305705.1
TIRAP	NM_148910.3	c.37C>T	p.Arg13Trp	missense_variant	4/5		NP_683708.1
TIRAP	NM_001039661.2	c.37C>T	p.Arg13Trp	missense_variant	4/6		NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.37C>T	p.Arg13Trp	missense_variant	3/5	2	NM_001318777.2	ENSP00000376446	P1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2257 AN: 152162 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.0242

Gnomad AMR AF: 0.00910

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00290

Gnomad FIN AF: 0.0390

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.0141 AC: 3374 AN: 239306 Hom.: 46 AF XY: 0.0142 AC XY: 1835 AN XY: 129354

Gnomad AFR exome AF: 0.00317

Gnomad AMR exome AF: 0.00563

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.000110

Gnomad SAS exome AF: 0.00292

Gnomad FIN exome AF: 0.0373

Gnomad NFE exome AF: 0.0193

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0186 AC: 27060 AN: 1454696 Hom.: 293 Cov.: 31 AF XY: 0.0182 AC XY: 13153 AN XY: 722950

Gnomad4 AFR exome AF: 0.00267

Gnomad4 AMR exome AF: 0.00618

Gnomad4 ASJ exome AF: 0.0125

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00325

Gnomad4 FIN exome AF: 0.0364

Gnomad4 NFE exome AF: 0.0210

Gnomad4 OTH exome AF: 0.0148

GnomAD4 genome AF: 0.0148 AC: 2258 AN: 152280 Hom.: 23 Cov.: 32 AF XY: 0.0145 AC XY: 1079 AN XY: 74452

Gnomad4 AFR AF: 0.00380

Gnomad4 AMR AF: 0.00909

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.0390

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.0187 Hom.: 49

Bravo AF: 0.0123

TwinsUK AF: 0.0181 AC: 67

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00500 AC: 22

ESP6500EA AF: 0.0194 AC: 167

ExAC AF: 0.0134 AC: 1629

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.098	T;.;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.85	.;D;.
MetaRNN	Benign	0.0019	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.13	N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0080	D;D;D
Polyphen		0.98	D;.;D
Vest4		0.11
MPC		0.14
ClinPred		0.022	T
GERP RS		0.90
Varity_R		0.061
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs8177399; hg19: chr11-126160826; COSMIC: COSV99071664; COSMIC: COSV99071664;