chr11-126292695-G-A

Position:

• chr11-126292695-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP3 BP4_Strong BP6_Moderate BS2

The NM_001318777.2(TIRAP):​c.286G>A​(p.Asp96Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00226 in 1,613,862 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (15 hom.)
• Consequence: TIRAP NM_001318777.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• 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 Benign. Variant got -9 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, Dann, Eigen, FATHMM_MKL, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, BayesDel_noAF, max_spliceai, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.037235945).
• BP6: Variant 11-126292695-G-A is Benign according to our data. Variant chr11-126292695-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1285058.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-126292695-G-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.286G>A	p.Asp96Asn	missense_variant	4/5	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.286G>A	p.Asp96Asn	missense_variant	4/4		NP_001305705.1
TIRAP	NM_148910.3	c.286G>A	p.Asp96Asn	missense_variant	5/5		NP_683708.1
TIRAP	NM_001039661.2	c.286G>A	p.Asp96Asn	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>A	p.Asp96Asn	missense_variant	4/5	2	NM_001318777.2	ENSP00000376446.1

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152218 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.00383

GnomAD3 exomes AF: 0.00276 AC: 691 AN: 250018 Hom.: 4 AF XY: 0.00313 AC XY: 423 AN XY: 135254

Gnomad AFR exome AF: 0.000249

Gnomad AMR exome AF: 0.00212

Gnomad ASJ exome AF: 0.0118

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00514

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00276

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00227 AC: 3316 AN: 1461526 Hom.: 15 Cov.: 31 AF XY: 0.00250 AC XY: 1821 AN XY: 727032

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.0122

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00515

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.00194

Gnomad4 OTH exome AF: 0.00349

GnomAD4 genome AF: 0.00214 AC: 326 AN: 152336 Hom.: 1 Cov.: 32 AF XY: 0.00189 AC XY: 141 AN XY: 74490

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00203

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.00379

Alfa AF: 0.00327 Hom.: 4

Bravo AF: 0.00235

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00287 AC: 349

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00447

EpiControl AF: 0.00486

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;.;T
Eigen	Pathogenic	0.82
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	.;T;.
MetaRNN	Benign	0.037	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M;M
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.94
MVP		0.76
MPC		0.22
ClinPred		0.040	T
GERP RS		5.4
Varity_R		0.96
gMVP		0.85

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;