19-4817276-AAGGAGGAGGAGG-AAGGAGGAGGAGGAGG

Variant names:

• chr19-4817276-A-AAGG
• rs11466722
• NM_182919.4:c.1099_1101dupCCT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_182919.4(TICAM1):​c.1099_1101dupCCT​(p.Pro367dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.146 in 1,602,862 control chromosomes in the GnomAD database, including 14,261 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2408 hom., cov: 27)
  • Exomes 𝑓: 0.14 (11853 hom.)
• Consequence: TICAM1 NM_182919.4 conservative_inframe_insertion
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.90
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-4817276-A-AAGG is Benign according to our data. Variant chr19-4817276-A-AAGG is described in ClinVar as Benign. ClinVar VariationId is 403541.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

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.1099_1101dupCCT	p.Pro367dup	conservative_inframe_insertion	Exon 2 of 2	NP_891549.1	Q8IUC6
	TICAM1	NM_001385678.1		c.1057_1059dupCCT	p.Pro353dup	conservative_inframe_insertion	Exon 3 of 3	NP_001372607.1
	TICAM1	NM_001385679.1		c.964_966dupCCT	p.Pro322dup	conservative_inframe_insertion	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.1099_1101dupCCT	p.Pro367dup	conservative_inframe_insertion	Exon 2 of 2	ENSP00000248244.4	Q8IUC6
	TICAM1	ENST00000868535.1		c.1099_1101dupCCT	p.Pro367dup	conservative_inframe_insertion	Exon 3 of 3	ENSP00000538594.1

Frequencies

GnomAD3 genomes AF: 0.167 AC: 24621 AN: 147376 Hom.: 2414 Cov.: 27

Gnomad AFR AF: 0.265

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.0777

Gnomad SAS AF: 0.125

Gnomad FIN AF: 0.0596

Gnomad MID AF: 0.222

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.178

GnomAD2 exomes AF: 0.136 AC: 33416 AN: 246324 AF XY: 0.137

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.0920

Gnomad ASJ exome AF: 0.175

Gnomad EAS exome AF: 0.0926

Gnomad FIN exome AF: 0.0722

Gnomad NFE exome AF: 0.147

Gnomad OTH exome AF: 0.144

GnomAD4 exome AF: 0.144 AC: 208911 AN: 1455370 Hom.: 11853 Cov.: 61 AF XY: 0.143 AC XY: 103759 AN XY: 724058

African (AFR) AF: 0.279 AC: 9208 AN: 33030

American (AMR) AF: 0.0975 AC: 4349 AN: 44626

Ashkenazi Jewish (ASJ) AF: 0.169 AC: 4378 AN: 25976

East Asian (EAS) AF: 0.0803 AC: 3185 AN: 39648

South Asian (SAS) AF: 0.131 AC: 11255 AN: 85958

European-Finnish (FIN) AF: 0.0760 AC: 4047 AN: 53276

Middle Eastern (MID) AF: 0.193 AC: 1093 AN: 5662

European-Non Finnish (NFE) AF: 0.147 AC: 162307 AN: 1107100

Other (OTH) AF: 0.151 AC: 9089 AN: 60094

GnomAD4 genome AF: 0.167 AC: 24625 AN: 147492 Hom.: 2408 Cov.: 27 AF XY: 0.162 AC XY: 11670 AN XY: 71974

African (AFR) AF: 0.265 AC: 10300 AN: 38862

American (AMR) AF: 0.123 AC: 1829 AN: 14824

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 572 AN: 3442

East Asian (EAS) AF: 0.0779 AC: 394 AN: 5056

South Asian (SAS) AF: 0.125 AC: 583 AN: 4658

European-Finnish (FIN) AF: 0.0596 AC: 611 AN: 10258

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9790 AN: 67152

Other (OTH) AF: 0.176 AC: 361 AN: 2052

Alfa AF: 0.0849 Hom.: 133

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.9
Mutation Taster		=82/18	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11466722; hg19: chr19-4817288; COSMIC: COSV50229566;