11-126292695-G-A

Variant names:

• chr11-126292695-G-A
• rs8177400
• NM_001318777.2:c.286G>A

Variant summary

Our verdict is Benign. The variant received -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 (★).

• 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
• Publications: 34 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 -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 VariationId is 1285058.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 15 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.286G>A	p.Asp96Asn	missense	Exon 4 of 5	NP_001305706.1
	TIRAP	NM_001318776.2		c.286G>A	p.Asp96Asn	missense	Exon 4 of 4	NP_001305705.1
	TIRAP	NM_148910.3		c.286G>A	p.Asp96Asn	missense	Exon 5 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.286G>A	p.Asp96Asn	missense	Exon 4 of 5	ENSP00000376446.1
	TIRAP	ENST00000392678.7	TSL:1	c.286G>A	p.Asp96Asn	missense	Exon 5 of 5	ENSP00000376445.3
	TIRAP	ENST00000392680.6	TSL:1	c.286G>A	p.Asp96Asn	missense	Exon 5 of 6	ENSP00000376447.2

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

GnomAD2 exomes AF: 0.00276 AC: 691 AN: 250018 AF XY: 0.00313

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 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

African (AFR) AF: 0.000239 AC: 8 AN: 33472

American (AMR) AF: 0.00237 AC: 106 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 319 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39676

South Asian (SAS) AF: 0.00515 AC: 444 AN: 86196

European-Finnish (FIN) AF: 0.000169 AC: 9 AN: 53350

Middle Eastern (MID) AF: 0.0114 AC: 66 AN: 5768

European-Non Finnish (NFE) AF: 0.00194 AC: 2152 AN: 1111866

Other (OTH) AF: 0.00349 AC: 211 AN: 60382

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

African (AFR) AF: 0.000361 AC: 15 AN: 41586

American (AMR) AF: 0.00203 AC: 31 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00294 AC: 200 AN: 68032

Other (OTH) AF: 0.00379 AC: 8 AN: 2112

Alfa AF: 0.00290 Hom.: 7

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

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M
PhyloP100		8.5
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	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
Mutation Taster		=76/24	polymorphism

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: rs8177400; hg19: chr11-126162590;