19-4816384-G-C

Variant names:

• chr19-4816384-G-C
• rs779499603
• NM_182919.4:c.1994C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_182919.4(TICAM1):​c.1994C>G​(p.Thr665Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000158 in 1,586,690 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.03
• Publications: 3 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07197645).

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.1994C>G	p.Thr665Arg	missense	Exon 2 of 2	NP_891549.1	Q8IUC6
	TICAM1	NM_001385678.1		c.1952C>G	p.Thr651Arg	missense	Exon 3 of 3	NP_001372607.1
	TICAM1	NM_001385679.1		c.1859C>G	p.Thr620Arg	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.1994C>G	p.Thr665Arg	missense	Exon 2 of 2	ENSP00000248244.4	Q8IUC6
	TICAM1	ENST00000868535.1		c.1994C>G	p.Thr665Arg	missense	Exon 3 of 3	ENSP00000538594.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000447 AC: 1 AN: 223764 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000572

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000167 AC: 24 AN: 1434414 Hom.: 0 Cov.: 36 AF XY: 0.0000183 AC XY: 13 AN XY: 711724

African (AFR) AF: 0.00 AC: 0 AN: 32586

American (AMR) AF: 0.00 AC: 0 AN: 40194

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23962

East Asian (EAS) AF: 0.000607 AC: 24 AN: 39554

South Asian (SAS) AF: 0.00 AC: 0 AN: 82020

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5562

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1099408

Other (OTH) AF: 0.00 AC: 0 AN: 59272

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74444

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2112

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Herpes simplex encephalitis, susceptibility to, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	4.1
DANN	Benign	0.84
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.072	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-1.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-0.81	N
REVEL	Benign	0.038
Sift	Uncertain	0.022	D
Sift4G	Benign	0.29	T
Polyphen		0.14	B
Vest4		0.18
MutPred		0.15		Loss of glycosylation at T665 (P = 8e-04)
MVP		0.13
MPC		0.34
ClinPred		0.029	T
GERP RS		-0.22
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
Mutation Taster		=89/11	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: rs779499603; hg19: chr19-4816396;