chr11-126292477-A-G

Position:

• chr11-126292477-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001318777.2(TIRAP):​c.68A>G​(p.Asp23Gly) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TIRAP NM_001318777.2 missense, splice_region
• Scores: Splicing: ADA: 0.00004056
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.89

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.129343).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIRAP	NM_001318777.2	c.68A>G	p.Asp23Gly	missense_variant, splice_region_variant	4/5	ENST00000392679.6	NP_001305706.1
TIRAP	NM_001318776.2	c.68A>G	p.Asp23Gly	missense_variant, splice_region_variant	4/4		NP_001305705.1
TIRAP	NM_148910.3	c.68A>G	p.Asp23Gly	missense_variant, splice_region_variant	5/5		NP_683708.1
TIRAP	NM_001039661.2	c.68A>G	p.Asp23Gly	missense_variant, splice_region_variant	5/6		NP_001034750.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIRAP	ENST00000392679.6	c.68A>G	p.Asp23Gly	missense_variant, splice_region_variant	4/5	2	NM_001318777.2	ENSP00000376446.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461600 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727080

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 28, 2024

The c.68A>G (p.D23G) alteration is located in exon 5 (coding exon 2) of the TIRAP gene. This alteration results from a A to G substitution at nucleotide position 68, causing the aspartic acid (D) at amino acid position 23 to be replaced by a glycine (G). 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	Benign	0.12
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	14
DANN	Benign	0.79
DEOGEN2	Benign	0.092	T;.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.52	D
LIST_S2	Benign	0.70	.;T;.
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M;M;M
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.59	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.29	T;T;T
Sift4G	Benign	0.66	T;T;T
Polyphen		0.0020	B;.;B
Vest4		0.16
MutPred		0.16		Loss of stability (P = 0.1062);Loss of stability (P = 0.1062);Loss of stability (P = 0.1062);
MVP		0.51
MPC		0.035
ClinPred		0.24	T
GERP RS		1.4
Varity_R		0.098
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000041
dbscSNV1_RF	Benign	0.0
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: rs201470535; hg19: chr11-126162372;