chr19-4816676-C-T

Position:

• chr19-4816676-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_182919.4(TICAM1):​c.1702G>A​(p.Ala568Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00318 in 1,614,110 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0027 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0032 (14 hom.)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5 O:1
• Conservation: PhyloP100: -0.814

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0057742894).
• BP6: Variant 19-4816676-C-T is Benign according to our data. Variant chr19-4816676-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473292.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}. Variant chr19-4816676-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 3 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICAM1	NM_182919.4	c.1702G>A	p.Ala568Thr	missense_variant	2/2	ENST00000248244.6	NP_891549.1
TICAM1	NM_001385678.1	c.1660G>A	p.Ala554Thr	missense_variant	3/3		NP_001372607.1
TICAM1	NM_001385679.1	c.1567G>A	p.Ala523Thr	missense_variant	2/2		NP_001372608.1
TICAM1	NM_001385680.1	c.1060G>A	p.Ala354Thr	missense_variant	3/3		NP_001372609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICAM1	ENST00000248244.6	c.1702G>A	p.Ala568Thr	missense_variant	2/2	1	NM_182919.4	ENSP00000248244.4

Frequencies

GnomAD3 genomes AF: 0.00272 AC: 414 AN: 152224 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.0143

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00412

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.00300 AC: 753 AN: 251200 Hom.: 4 AF XY: 0.00346 AC XY: 470 AN XY: 135852

Gnomad AFR exome AF: 0.000431

Gnomad AMR exome AF: 0.00127

Gnomad ASJ exome AF: 0.00864

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.00116

Gnomad NFE exome AF: 0.00400

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00322 AC: 4712 AN: 1461770 Hom.: 14 Cov.: 43 AF XY: 0.00329 AC XY: 2396 AN XY: 727180

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00804

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00370

Gnomad4 FIN exome AF: 0.00133

Gnomad4 NFE exome AF: 0.00338

Gnomad4 OTH exome AF: 0.00361

GnomAD4 genome AF: 0.00272 AC: 415 AN: 152340 Hom.: 3 Cov.: 33 AF XY: 0.00268 AC XY: 200 AN XY: 74492

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.00122

Gnomad4 NFE AF: 0.00412

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00388 Hom.: 3

Bravo AF: 0.00243

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00309 AC: 375

EpiCase AF: 0.00485

EpiControl AF: 0.00486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 4 Uncertain:1 Benign:1 Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	TICAM1 NM_182919.3 exon 2 p.Ala568Thr (c.1702G>A): This variant has been reported in the literature in at least 1 individual with a history of Herpes simplex encephalitis (HSE) (Mork 2015 PMID:26513235, Andersen 2019 PMID:29217828). This variant is present in 0.3% (503/128998) of European alleles, including 1 homozygote in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/19-4816688-C-T?dataset=gnomad_r2_1). This variant is present in ClinVar (Variation ID:473292). This variant amino acid Threonine (Thr) is present in 5 species (Pika, Elephant, Saker falcon, Peregrine falcon, Atlantic cod) and is not well conserved among evolutionarily distant species; this suggests that this variant may not impact the protein. Additional computational prediction tools do not suggest an impact. In vitro functional studies suggest that this variant will impact the protein (Andersen 2019 PMID:29217828). However, these studies may not accurately represent in vivo biological function. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -
risk factor, no assertion criteria provided	literature only	OMIM	Mar 15, 2018	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2023	TICAM1: BP4, BS2 -

TICAM1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 13, 2024

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	1.6
DANN	Benign	0.73
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.98
FATHMM_MKL	Benign	0.059	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.0058	T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.6	L;.
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.026
Sift	Benign	0.10	T;.
Sift4G	Uncertain	0.037	D;D
Polyphen		0.25	B;.
Vest4		0.13
MVP		0.19
MPC		0.22
ClinPred		0.0022	T
GERP RS		-1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.040

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: rs143679494; hg19: chr19-4816688;