11-126292998-G-A

Position:

• chr11-126292998-G-A

Variant summary

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

The NM_001318777.2(TIRAP):​c.589G>A​(p.Val197Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00175 in 1,614,176 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 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 0.0076 (14 hom., cov: 33)
  • Exomes 𝑓: 0.0011 (14 hom.)
• Consequence: TIRAP NM_001318777.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004019141).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0076 (1158/152326) while in subpopulation AFR AF= 0.0247 (1027/41572). AF 95% confidence interval is 0.0234. There are 14 homozygotes in gnomad4. There are 520 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIRAP	NM_001318777.2	c.589G>A	p.Val197Ile	missense_variant	4/5	ENST00000392679.6
TIRAP	NM_001318776.2	c.589G>A	p.Val197Ile	missense_variant	4/4
TIRAP	NM_148910.3	c.589G>A	p.Val197Ile	missense_variant	5/5
TIRAP	NM_001039661.2	c.589G>A	p.Val197Ile	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIRAP	ENST00000392679.6	c.589G>A	p.Val197Ile	missense_variant	4/5	2	NM_001318777.2	P1
	ENST00000533378.1	n.416C>T		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.00754 AC: 1147 AN: 152208 Hom.: 12 Cov.: 33

Gnomad AFR AF: 0.0245

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000632

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00231 AC: 577 AN: 249838 Hom.: 6 AF XY: 0.00176 AC XY: 238 AN XY: 135502

Gnomad AFR exome AF: 0.0249

Gnomad AMR exome AF: 0.00310

Gnomad ASJ exome AF: 0.00149

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000459

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00114 AC: 1668 AN: 1461850 Hom.: 14 Cov.: 34 AF XY: 0.000971 AC XY: 706 AN XY: 727230

Gnomad4 AFR exome AF: 0.0260

Gnomad4 AMR exome AF: 0.00353

Gnomad4 ASJ exome AF: 0.00115

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000371

Gnomad4 OTH exome AF: 0.00267

GnomAD4 genome AF: 0.00760 AC: 1158 AN: 152326 Hom.: 14 Cov.: 33 AF XY: 0.00698 AC XY: 520 AN XY: 74494

Gnomad4 AFR AF: 0.0247

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000632

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00190 Hom.: 2

Bravo AF: 0.00864

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0264 AC: 116

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00259 AC: 314

Asia WGS AF: 0.00577 AC: 21 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000415

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.050	T;.;T
Eigen	Benign	0.083
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.74	.;T;.
MetaRNN	Benign	0.0040	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	0.58	N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.12	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.45	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.88	P;.;P
Vest4		0.10
MVP		0.46
MPC		0.21
ClinPred		0.031	T
GERP RS		3.9
Varity_R		0.085
gMVP		0.24

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: rs7932976; hg19: chr11-126162893; COSMIC: COSV101201628; COSMIC: COSV101201628;