chr19-4817645-C-A

Position:

• chr19-4817645-C-A

Variant summary

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

The ENST00000248244.6(TICAM1):​c.733G>T​(p.Gly245Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G245S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TICAM1 ENST00000248244.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.13

Genes affected

TICAM1 (HGNC:18348): (TIR domain containing adaptor molecule 1) This gene encodes an adaptor protein containing a Toll/interleukin-1 receptor (TIR) homology domain, which is an intracellular signaling domain that mediates protein-protein interactions between the Toll-like receptors (TLRs) and signal-transduction components. This protein is involved in native immunity against invading pathogens. It specifically interacts with toll-like receptor 3, but not with other TLRs, and this association mediates dsRNA induction of interferon-beta through activation of nuclear factor kappa-B, during an antiviral immune response. Mutations in this gene are associated with encephalopathy, acute, infection-induced. [provided by RefSeq, Jul 2020]

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=0.09736681).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICAM1	NM_182919.4	c.733G>T	p.Gly245Cys	missense_variant	2/2	ENST00000248244.6	NP_891549.1
TICAM1	NM_001385678.1	c.691G>T	p.Gly231Cys	missense_variant	3/3		NP_001372607.1
TICAM1	NM_001385679.1	c.598G>T	p.Gly200Cys	missense_variant	2/2		NP_001372608.1
TICAM1	NM_001385680.1	c.91G>T	p.Gly31Cys	missense_variant	3/3		NP_001372609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICAM1	ENST00000248244.6	c.733G>T	p.Gly245Cys	missense_variant	2/2	1	NM_182919.4	ENSP00000248244	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 79

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.022
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.082	N
LIST_S2	Benign	0.47	T;T
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.097	T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.7	N;.
REVEL	Benign	0.11
Sift	Benign	0.055	T;.
Sift4G	Uncertain	0.051	T;T
Polyphen		0.91	P;.
Vest4		0.17
MutPred		0.18		Gain of catalytic residue at P244 (P = 0.0073);.;
MVP		0.12
MPC		0.46
ClinPred		0.37	T
GERP RS		-5.1
Varity_R		0.093

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: rs151272128; hg19: chr19-4817657; COSMIC: COSV105064236;