11-126292811-C-G

Variant names:

• chr11-126292811-C-G
• rs771728710
• NM_001318777.2:c.402C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001318777.2(TIRAP):​c.402C>G​(p.Cys134Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,650 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TIRAP NM_001318777.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.992

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.81

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.402C>G	p.Cys134Trp	missense_variant	Exon 4 of 5	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.402C>G	p.Cys134Trp	missense_variant	Exon 4 of 4		NP_001305705.1
TIRAP	NM_148910.3	c.402C>G	p.Cys134Trp	missense_variant	Exon 5 of 5		NP_683708.1
TIRAP	NM_001039661.2	c.402C>G	p.Cys134Trp	missense_variant	Exon 5 of 6		NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.402C>G	p.Cys134Trp	missense_variant	Exon 4 of 5	2	NM_001318777.2	ENSP00000376446.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000403 AC: 1 AN: 248378 Hom.: 0 AF XY: 0.00000743 AC XY: 1 AN XY: 134500

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460650 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726582

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.402C>G (p.C134W) alteration is located in exon 5 (coding exon 2) of the TIRAP gene. This alteration results from a C to G substitution at nucleotide position 402, causing the cysteine (C) at amino acid position 134 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.69	.;T;.
M_CAP	Benign	0.026	D
MetaRNN	Pathogenic	0.81	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.7	D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.79
MutPred		0.48		Gain of catalytic residue at C134 (P = 0.0328);Gain of catalytic residue at C134 (P = 0.0328);Gain of catalytic residue at C134 (P = 0.0328);
MVP		0.79
MPC		0.24
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.95
gMVP		0.80

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: rs771728710; hg19: chr11-126162706;