NM_182919.4:c.223C>T

Variant names:

• chr19-4818155-G-A
• rs11466719
• NM_182919.4:c.223C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_182919.4(TICAM1):​c.223C>T​(p.Arg75Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00094 in 1,609,320 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R75S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (4 hom.)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.124
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035818815).
• BP6: Variant 19-4818155-G-A is Benign according to our data. Variant chr19-4818155-G-A is described in ClinVar as Benign. ClinVar VariationId is 540514.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000586 (854/1456982) while in subpopulation AFR AF = 0.0162 (542/33462). AF 95% confidence interval is 0.0151. There are 4 homozygotes in GnomAdExome4. There are 352 alleles in the male GnomAdExome4 subpopulation. Median coverage is 81. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.223C>T	p.Arg75Cys	missense	Exon 2 of 2	NP_891549.1
	TICAM1	NM_001385678.1		c.181C>T	p.Arg61Cys	missense	Exon 3 of 3	NP_001372607.1
	TICAM1	NM_001385679.1		c.88C>T	p.Arg30Cys	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.223C>T	p.Arg75Cys	missense	Exon 2 of 2	ENSP00000248244.4
	TICAM1	ENST00000868535.1		c.223C>T	p.Arg75Cys	missense	Exon 3 of 3	ENSP00000538594.1

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 655 AN: 152220 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.000103

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00112 AC: 267 AN: 238856 AF XY: 0.000864

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.000557

Gnomad ASJ exome AF: 0.000918

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000834

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000586 AC: 854 AN: 1456982 Hom.: 4 Cov.: 81 AF XY: 0.000486 AC XY: 352 AN XY: 724994

African (AFR) AF: 0.0162 AC: 542 AN: 33462

American (AMR) AF: 0.000583 AC: 26 AN: 44562

Ashkenazi Jewish (ASJ) AF: 0.00123 AC: 32 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39660

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49468

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5760

European-Non Finnish (NFE) AF: 0.000148 AC: 165 AN: 1111546

Other (OTH) AF: 0.00125 AC: 75 AN: 60240

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152338 Hom.: 4 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74484

African (AFR) AF: 0.0151 AC: 626 AN: 41580

American (AMR) AF: 0.000981 AC: 15 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

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

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00145 Hom.: 39

Bravo AF: 0.00496

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0167 AC: 73

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.00134 AC: 162

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.12
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.031
Sift	Benign	0.090	T
Sift4G	Uncertain	0.014	D
Polyphen		0.013	B
Vest4		0.17
MVP		0.15
MPC		0.30
ClinPred		0.0086	T
GERP RS		0.96
Varity_R		0.17
Mutation Taster		=92/8	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: rs11466719; hg19: chr19-4818167;