rs2292151

Positions:

• chr19-4816707-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_182919.4(TICAM1):​c.1671C>T​(p.Asp557Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.251 in 1,613,854 control chromosomes in the GnomAD database, including 53,027 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (4939 hom., cov: 33)
  • Exomes 𝑓: 0.25 (48088 hom.)
• Consequence: TICAM1 NM_182919.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.386

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-4816707-G-A is Benign according to our data. Variant chr19-4816707-G-A is described in ClinVar as [Benign]. Clinvar id is 403540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4816707-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.386 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICAM1	NM_182919.4	c.1671C>T	p.Asp557Asp	synonymous_variant	2/2	ENST00000248244.6	NP_891549.1
TICAM1	NM_001385678.1	c.1629C>T	p.Asp543Asp	synonymous_variant	3/3		NP_001372607.1
TICAM1	NM_001385679.1	c.1536C>T	p.Asp512Asp	synonymous_variant	2/2		NP_001372608.1
TICAM1	NM_001385680.1	c.1029C>T	p.Asp343Asp	synonymous_variant	3/3		NP_001372609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICAM1	ENST00000248244.6	c.1671C>T	p.Asp557Asp	synonymous_variant	2/2	1	NM_182919.4	ENSP00000248244.4

Frequencies

GnomAD3 genomes AF: 0.242 AC: 36781 AN: 152070 Hom.: 4935 Cov.: 33

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.290

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.422

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.368

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.242

Gnomad OTH AF: 0.243

GnomAD3 exomes AF: 0.274 AC: 68834 AN: 251030 Hom.: 10009 AF XY: 0.272 AC XY: 36869 AN XY: 135774

Gnomad AFR exome AF: 0.167

Gnomad AMR exome AF: 0.341

Gnomad ASJ exome AF: 0.236

Gnomad EAS exome AF: 0.414

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.238

Gnomad OTH exome AF: 0.273

GnomAD4 exome AF: 0.252 AC: 368104 AN: 1461666 Hom.: 48088 Cov.: 82 AF XY: 0.251 AC XY: 182755 AN XY: 727134

Gnomad4 AFR exome AF: 0.166

Gnomad4 AMR exome AF: 0.340

Gnomad4 ASJ exome AF: 0.242

Gnomad4 EAS exome AF: 0.458

Gnomad4 SAS exome AF: 0.259

Gnomad4 FIN exome AF: 0.355

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.250

GnomAD4 genome AF: 0.242 AC: 36801 AN: 152188 Hom.: 4939 Cov.: 33 AF XY: 0.249 AC XY: 18559 AN XY: 74396

Gnomad4 AFR AF: 0.169

Gnomad4 AMR AF: 0.290

Gnomad4 ASJ AF: 0.231

Gnomad4 EAS AF: 0.422

Gnomad4 SAS AF: 0.269

Gnomad4 FIN AF: 0.368

Gnomad4 NFE AF: 0.242

Gnomad4 OTH AF: 0.240

Alfa AF: 0.240 Hom.: 9079

Bravo AF: 0.234

Asia WGS AF: 0.324 AC: 1127 AN: 3478

EpiCase AF: 0.232

EpiControl AF: 0.233

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jan 24, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 62% of patients studied by a panel of primary immunodeficiencies. Number of patients: 59. Only high quality variants are reported. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Herpes simplex encephalitis, susceptibility to, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.0
DANN	Benign	0.84

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

Publications

LitVar

Other links and lift over

dbSNP: rs2292151; hg19: chr19-4816719; COSMIC: COSV50229420;