rs146550489

Variant names:

• chr19-4817821-G-A
• rs146550489
• NM_182919.4:c.557C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_182919.4(TICAM1):​c.557C>T​(p.Ser186Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000239 in 1,604,790 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. S186S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00058 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 O:1
• Conservation: PhyloP100: 0.751
• Publications: 9 publications found

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]

TICAM1 Gene-Disease associations (from GenCC):

• herpes simplex encephalitis, susceptibility to, 4

  Inheritance: AR, AD, SD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01178211).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182919.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICAM1	NM_182919.4	MANE Select	c.557C>T	p.Ser186Leu	missense	Exon 2 of 2	NP_891549.1	Q8IUC6
	TICAM1	NM_001385678.1		c.515C>T	p.Ser172Leu	missense	Exon 3 of 3	NP_001372607.1
	TICAM1	NM_001385679.1		c.422C>T	p.Ser141Leu	missense	Exon 2 of 2	NP_001372608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICAM1	ENST00000248244.6	TSL:1 MANE Select	c.557C>T	p.Ser186Leu	missense	Exon 2 of 2	ENSP00000248244.4	Q8IUC6
	TICAM1	ENST00000868535.1		c.557C>T	p.Ser186Leu	missense	Exon 3 of 3	ENSP00000538594.1

Frequencies

GnomAD3 genomes AF: 0.000592 AC: 90 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000307 AC: 74 AN: 241128 AF XY: 0.000268

Gnomad AFR exome AF: 0.00124

Gnomad AMR exome AF: 0.000410

Gnomad ASJ exome AF: 0.00210

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.000671

GnomAD4 exome AF: 0.000203 AC: 295 AN: 1452532 Hom.: 0 Cov.: 77 AF XY: 0.000191 AC XY: 138 AN XY: 722002

African (AFR) AF: 0.000659 AC: 22 AN: 33388

American (AMR) AF: 0.000474 AC: 21 AN: 44314

Ashkenazi Jewish (ASJ) AF: 0.00195 AC: 50 AN: 25654

East Asian (EAS) AF: 0.00 AC: 0 AN: 39600

South Asian (SAS) AF: 0.0000350 AC: 3 AN: 85688

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49590

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5744

European-Non Finnish (NFE) AF: 0.000149 AC: 165 AN: 1108470

Other (OTH) AF: 0.000483 AC: 29 AN: 60084

GnomAD4 genome AF: 0.000585 AC: 89 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74444

African (AFR) AF: 0.00128 AC: 53 AN: 41546

American (AMR) AF: 0.000982 AC: 15 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67996

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000368 Hom.: 1

Bravo AF: 0.000831

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000321 AC: 39

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	Herpes simplex encephalitis, susceptibility to, 4 (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	9.8
DANN	Benign	0.97
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.0068	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.90	L
PhyloP100		0.75
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.25
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.065	T
Polyphen		0.0	B
Vest4		0.12
MVP		0.76
MPC		0.20
ClinPred		0.012	T
GERP RS		1.1
Varity_R		0.062
Mutation Taster		=97/3	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: rs146550489; hg19: chr19-4817833;