19-4816676-C-T

Variant names:

• chr19-4816676-C-T
• rs143679494
• NM_182919.4:c.1702G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_182919.4(TICAM1):​c.1702G>A​(p.Ala568Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,614,110 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (14 hom.)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: -0.814
• Publications: 11 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, SD, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057742894).
• BP6: Variant 19-4816676-C-T is Benign according to our data. Variant chr19-4816676-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 473292.
• BS2: High Homozygotes in GnomAd4 at 3 AR,SD,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICAM1	NM_182919.4	MANE Select	c.1702G>A	p.Ala568Thr	missense	Exon 2 of 2	NP_891549.1
	TICAM1	NM_001385678.1		c.1660G>A	p.Ala554Thr	missense	Exon 3 of 3	NP_001372607.1
	TICAM1	NM_001385679.1		c.1567G>A	p.Ala523Thr	missense	Exon 2 of 2	NP_001372608.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICAM1	ENST00000248244.6	TSL:1 MANE Select	c.1702G>A	p.Ala568Thr	missense	Exon 2 of 2	ENSP00000248244.4

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152224 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00412

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00300 AC: 753 AN: 251200 AF XY: 0.00346

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00864

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00400

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00322 AC: 4712 AN: 1461770 Hom.: 14 Cov.: 43 AF XY: 0.00329 AC XY: 2396 AN XY: 727180

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00143 AC: 64 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00804 AC: 210 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00370 AC: 319 AN: 86258

European-Finnish (FIN) AF: 0.00133 AC: 71 AN: 53306

Middle Eastern (MID) AF: 0.00885 AC: 51 AN: 5764

European-Non Finnish (NFE) AF: 0.00338 AC: 3761 AN: 1112010

Other (OTH) AF: 0.00361 AC: 218 AN: 60396

GnomAD4 genome AF: 0.00272 AC: 415 AN: 152340 Hom.: 3 Cov.: 33 AF XY: 0.00268 AC XY: 200 AN XY: 74492

African (AFR) AF: 0.000577 AC: 24 AN: 41596

American (AMR) AF: 0.00157 AC: 24 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4830

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10624

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00412 AC: 280 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00363 Hom.: 5

Bravo AF: 0.00243

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00309 AC: 375

EpiCase AF: 0.00485

EpiControl AF: 0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 4 Uncertain:1 Benign:2 Other:1

Mar 15, 2018

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 30, 2021

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TICAM1 NM_182919.3 exon 2 p.Ala568Thr (c.1702G>A): This variant has been reported in the literature in at least 1 individual with a history of Herpes simplex encephalitis (HSE) (Mork 2015 PMID:26513235, Andersen 2019 PMID:29217828). This variant is present in 0.3% (503/128998) of European alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-4816688-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:473292). This variant amino acid Threonine (Thr) is present in 5 species (Pika, Elephant, Saker falcon, Peregrine falcon, Atlantic cod) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In vitro functional studies suggest that this variant will impact the protein (Andersen 2019 PMID:29217828). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain.

Feb 06, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: research

not provided Benign:3

Jul 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TICAM1: BP4, BS2

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

TICAM1-related disorder Benign:1

Aug 13, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.6
DANN	Benign	0.73
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0058	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.81
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.026
Sift	Benign	0.10	T
Sift4G	Uncertain	0.037	D
Polyphen		0.25	B
Vest4		0.13
MVP		0.19
MPC		0.22
ClinPred		0.0022	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040
Mutation Taster		=100/0	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: rs143679494; hg19: chr19-4816688;