chr11-126290919-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_001318777.2(TIRAP):​c.25G>C​(p.Ala9Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,607,432 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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: 𝑓 0.0051 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (5 hom.)
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004031092).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00509 (775/152254) while in subpopulation AFR AF = 0.0172 (716/41556). AF 95% confidence interval is 0.0162. There are 8 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 gene

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>C	p.Ala9Pro	missense	Exon 3 of 5	NP_001305706.1
	TIRAP	NM_001318776.2		c.25G>C	p.Ala9Pro	missense	Exon 3 of 4	NP_001305705.1
	TIRAP	NM_148910.3		c.25G>C	p.Ala9Pro	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>C	p.Ala9Pro	missense	Exon 3 of 5	ENSP00000376446.1
	TIRAP	ENST00000392678.7	TSL:1	c.25G>C	p.Ala9Pro	missense	Exon 4 of 5	ENSP00000376445.3
	TIRAP	ENST00000392680.6	TSL:1	c.25G>C	p.Ala9Pro	missense	Exon 4 of 6	ENSP00000376447.2

Frequencies

GnomAD3 genomes AF: 0.00509 AC: 774 AN: 152136 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00156 AC: 374 AN: 240232 AF XY: 0.00121

Gnomad AFR exome AF: 0.0174

Gnomad AMR exome AF: 0.00187

Gnomad ASJ exome AF: 0.00135

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000176

Gnomad OTH exome AF: 0.00304

GnomAD4 exome AF: 0.000748 AC: 1088 AN: 1455178 Hom.: 5 Cov.: 31 AF XY: 0.000702 AC XY: 508 AN XY: 723194

African (AFR) AF: 0.0198 AC: 662 AN: 33400

American (AMR) AF: 0.00195 AC: 86 AN: 44070

Ashkenazi Jewish (ASJ) AF: 0.00128 AC: 33 AN: 25778

East Asian (EAS) AF: 0.00 AC: 0 AN: 39644

South Asian (SAS) AF: 0.0000706 AC: 6 AN: 84960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52878

Middle Eastern (MID) AF: 0.00678 AC: 39 AN: 5752

European-Non Finnish (NFE) AF: 0.000135 AC: 150 AN: 1108544

Other (OTH) AF: 0.00186 AC: 112 AN: 60152

GnomAD4 genome AF: 0.00509 AC: 775 AN: 152254 Hom.: 8 Cov.: 32 AF XY: 0.00453 AC XY: 337 AN XY: 74434

African (AFR) AF: 0.0172 AC: 716 AN: 41556

American (AMR) AF: 0.00177 AC: 27 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000235 AC: 16 AN: 68018

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00149 Hom.: 4

Bravo AF: 0.00611

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00170 AC: 206

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T
Eigen	Benign	-0.068
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.9	L
PhyloP100		1.1
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.82	N
REVEL	Benign	0.15
Sift	Benign	0.062	T
Sift4G	Benign	0.090	T
Polyphen		0.86	P
Vest4		0.32
MVP		0.58
MPC		0.090
ClinPred		0.017	T
GERP RS		3.1
Varity_R		0.12
gMVP		0.42
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;