19-4818366-T-C

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.12A>G(p.Thr4=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.65 in 1,599,354 control chromosomes in the GnomAD database, including 341,718 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T4T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.72 (40613 hom., cov: 33)
  • Exomes 𝑓: 0.64 (301105 hom.)
• Consequence: TICAM1 NM_182919.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3 O:1
• Conservation: PhyloP100: -4.35

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=-0.92).
• BP6: Variant 19-4818366-T-C is Benign according to our data. Variant chr19-4818366-T-C is described in ClinVar as [Benign]. Clinvar id is 403542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-4818366-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.35 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TICAM1	NM_182919.4	c.12A>G	p.Thr4=	synonymous_variant	2/2	ENST00000248244.6
TICAM1	NM_001385678.1	c.5-35A>G		intron_variant
TICAM1	NM_001385679.1	c.-89-35A>G		intron_variant
TICAM1	NM_001385680.1	c.-72+18A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICAM1	ENST00000248244.6	c.12A>G	p.Thr4=	synonymous_variant	2/2	1	NM_182919.4	P1

Frequencies

GnomAD3 genomes AF: 0.718 AC: 109257 AN: 152068 Hom.: 40560 Cov.: 33

Gnomad AFR AF: 0.924

Gnomad AMI AF: 0.493

Gnomad AMR AF: 0.683

Gnomad ASJ AF: 0.639

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.700

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.703

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.703

GnomAD3 exomes AF: 0.658 AC: 154814 AN: 235140 Hom.: 51545 AF XY: 0.656 AC XY: 84143 AN XY: 128206

Gnomad AFR exome AF: 0.928

Gnomad AMR exome AF: 0.657

Gnomad ASJ exome AF: 0.660

Gnomad EAS exome AF: 0.569

Gnomad SAS exome AF: 0.697

Gnomad FIN exome AF: 0.649

Gnomad NFE exome AF: 0.626

Gnomad OTH exome AF: 0.658

GnomAD4 exome AF: 0.642 AC: 929502 AN: 1447168 Hom.: 301105 Cov.: 63 AF XY: 0.643 AC XY: 462095 AN XY: 719048

Gnomad4 AFR exome AF: 0.936

Gnomad4 AMR exome AF: 0.662

Gnomad4 ASJ exome AF: 0.664

Gnomad4 EAS exome AF: 0.624

Gnomad4 SAS exome AF: 0.698

Gnomad4 FIN exome AF: 0.648

Gnomad4 NFE exome AF: 0.627

Gnomad4 OTH exome AF: 0.654

GnomAD4 genome AF: 0.719 AC: 109367 AN: 152186 Hom.: 40613 Cov.: 33 AF XY: 0.719 AC XY: 53497 AN XY: 74386

Gnomad4 AFR AF: 0.924

Gnomad4 AMR AF: 0.684

Gnomad4 ASJ AF: 0.639

Gnomad4 EAS AF: 0.592

Gnomad4 SAS AF: 0.699

Gnomad4 FIN AF: 0.663

Gnomad4 NFE AF: 0.628

Gnomad4 OTH AF: 0.701

Alfa AF: 0.642 Hom.: 56072

Bravo AF: 0.726

Asia WGS AF: 0.649 AC: 2256 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

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 -
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 92% of patients studied by a panel of primary immunodeficiencies. Number of patients: 87. Only high quality variants are reported. -

Herpes simplex encephalitis, susceptibility to, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpreted as Benign and reported on 04-27-2020 by Lab or GTR ID 500031. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. This variant was reported in an individual referred for clinical diagnostic genetic testing. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
Cadd	Benign	0.037
Dann	Benign	0.26

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: rs7255265; hg19: chr19-4818378; COSMIC: COSV50232725; COSMIC: COSV50232725;