11-126292948-C-T

Variant names:

• chr11-126292948-C-T
• rs8177374
• NM_001318777.2:c.539C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001318777.2(TIRAP):​c.539C>T​(p.Ser180Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.145 in 1,613,956 control chromosomes in the GnomAD database, including 18,397 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1228 hom., cov: 32)
  • Exomes 𝑓: 0.15 (17169 hom.)
• Consequence: TIRAP NM_001318777.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.751
• Publications: 200 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]

ENSG00000254905 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016107559).
• BP6: Variant 11-126292948-C-T is Benign according to our data. Variant chr11-126292948-C-T is described in ClinVar as Benign. ClinVar VariationId is 4467.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIRAP	NM_001318777.2	MANE Select	c.539C>T	p.Ser180Leu	missense	Exon 4 of 5	NP_001305706.1	P58753-1
	TIRAP	NM_001318776.2		c.539C>T	p.Ser180Leu	missense	Exon 4 of 4	NP_001305705.1	P58753-2
	TIRAP	NM_148910.3		c.539C>T	p.Ser180Leu	missense	Exon 5 of 5	NP_683708.1	P58753-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIRAP	ENST00000392679.6	TSL:2 MANE Select	c.539C>T	p.Ser180Leu	missense	Exon 4 of 5	ENSP00000376446.1	P58753-1
	TIRAP	ENST00000392678.7	TSL:1	c.539C>T	p.Ser180Leu	missense	Exon 5 of 5	ENSP00000376445.3	P58753-2
	TIRAP	ENST00000392680.6	TSL:1	c.539C>T	p.Ser180Leu	missense	Exon 5 of 6	ENSP00000376447.2	P58753-1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16910 AN: 152142 Hom.: 1228 Cov.: 32

Gnomad AFR AF: 0.0296

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.100

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.155

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.124

GnomAD2 exomes AF: 0.124 AC: 30945 AN: 250244 AF XY: 0.130

Gnomad AFR exome AF: 0.0262

Gnomad AMR exome AF: 0.0740

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0121

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.129

GnomAD4 exome AF: 0.148 AC: 216650 AN: 1461696 Hom.: 17169 Cov.: 34 AF XY: 0.149 AC XY: 108156 AN XY: 727136

African (AFR) AF: 0.0237 AC: 793 AN: 33480

American (AMR) AF: 0.0773 AC: 3456 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 3428 AN: 26134

East Asian (EAS) AF: 0.0200 AC: 794 AN: 39696

South Asian (SAS) AF: 0.157 AC: 13576 AN: 86246

European-Finnish (FIN) AF: 0.136 AC: 7274 AN: 53356

Middle Eastern (MID) AF: 0.139 AC: 799 AN: 5768

European-Non Finnish (NFE) AF: 0.160 AC: 178332 AN: 1111912

Other (OTH) AF: 0.136 AC: 8198 AN: 60388

GnomAD4 genome AF: 0.111 AC: 16904 AN: 152260 Hom.: 1228 Cov.: 32 AF XY: 0.111 AC XY: 8291 AN XY: 74450

African (AFR) AF: 0.0295 AC: 1225 AN: 41570

American (AMR) AF: 0.100 AC: 1528 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 453 AN: 3470

East Asian (EAS) AF: 0.0129 AC: 67 AN: 5188

South Asian (SAS) AF: 0.154 AC: 743 AN: 4826

European-Finnish (FIN) AF: 0.140 AC: 1489 AN: 10606

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10789 AN: 68008

Other (OTH) AF: 0.124 AC: 262 AN: 2112

Alfa AF: 0.140 Hom.: 6365

Bravo AF: 0.103

TwinsUK AF: 0.155 AC: 576

ALSPAC AF: 0.164 AC: 633

ESP6500AA AF: 0.0304 AC: 134

ESP6500EA AF: 0.158 AC: 1362

ExAC AF: 0.124 AC: 15074

Asia WGS AF: 0.0790 AC: 276 AN: 3478

EpiCase AF: 0.159

EpiControl AF: 0.158

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Mycobacterium tuberculosis, susceptibility to;C1970028:Malaria, susceptibility to;C3280645:Bacteremia, susceptibility to, 1 (1)
-	-	1	not specified (1)
-	-	-	Bacteremia, susceptibility (1)
-	-	-	Invasive pneumococcal disease, protection against (1)
-	-	-	Malaria, resistance to (1)
-	-	-	Mycobacterium tuberculosis, protection against (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	14
DANN	Benign	0.97
DEOGEN2	Benign	0.031	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.64	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.71	N
PhyloP100		0.75
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.092
Sift	Benign	0.53	T
Sift4G	Benign	0.24	T
Polyphen		0.46	P
Vest4		0.057
MPC		0.15
ClinPred		0.024	T
GERP RS		4.7
Varity_R		0.18
gMVP		0.47
Mutation Taster		=98/2	polymorphism (auto)

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: rs8177374; hg19: chr11-126162843; COSMIC: COSV67023783; COSMIC: COSV67023783;