rs199816697

Variant names:

• chr19-4818140-C-T
• rs199816697
• NM_182919.4:c.238G>A

Variant summary

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

The NM_182919.4(TICAM1):​c.238G>A​(p.Val80Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000701 in 1,609,628 control chromosomes in the GnomAD database, including 2 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00068 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00070 (1 hom.)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2 B:2
• Conservation: PhyloP100: -1.98
• 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, SD, AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0068617165).

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.238G>A	p.Val80Met	missense	Exon 2 of 2	NP_891549.1
	TICAM1	NM_001385678.1		c.196G>A	p.Val66Met	missense	Exon 3 of 3	NP_001372607.1
	TICAM1	NM_001385679.1		c.103G>A	p.Val35Met	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.238G>A	p.Val80Met	missense	Exon 2 of 2	ENSP00000248244.4

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152244 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000985

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000659 AC: 159 AN: 241402 AF XY: 0.000721

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000379

Gnomad ASJ exome AF: 0.000101

Gnomad EAS exome AF: 0.0000554

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00115

Gnomad OTH exome AF: 0.000672

GnomAD4 exome AF: 0.000703 AC: 1025 AN: 1457266 Hom.: 1 Cov.: 81 AF XY: 0.000707 AC XY: 513 AN XY: 725120

African (AFR) AF: 0.0000299 AC: 1 AN: 33462

American (AMR) AF: 0.000358 AC: 16 AN: 44632

Ashkenazi Jewish (ASJ) AF: 0.000268 AC: 7 AN: 26104

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39682

South Asian (SAS) AF: 0.000534 AC: 46 AN: 86204

European-Finnish (FIN) AF: 0.0000202 AC: 1 AN: 49414

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5766

European-Non Finnish (NFE) AF: 0.000801 AC: 890 AN: 1111684

Other (OTH) AF: 0.000746 AC: 45 AN: 60318

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152362 Hom.: 1 Cov.: 32 AF XY: 0.000617 AC XY: 46 AN XY: 74496

African (AFR) AF: 0.0000962 AC: 4 AN: 41588

American (AMR) AF: 0.00144 AC: 22 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000828 AC: 4 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000985 AC: 67 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000845 Hom.: 1

Bravo AF: 0.000669

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000677 AC: 82

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.000890

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	1	-	Herpes simplex encephalitis, susceptibility to, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.0060
DANN	Benign	0.81
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.52	T
M_CAP	Benign	0.0033	T
MetaRNN	Benign	0.0069	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	N
PhyloP100		-2.0
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.38	N
REVEL	Benign	0.012
Sift	Benign	0.69	T
Sift4G	Benign	0.29	T
Polyphen		0.066	B
Vest4		0.076
MVP		0.23
MPC		0.22
ClinPred		0.012	T
GERP RS		-9.2
Varity_R		0.12
Mutation Taster		=96/4	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: rs199816697; hg19: chr19-4818152; COSMIC: COSV50237202; COSMIC: COSV50237202;