19-4817645-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_182919.4(TICAM1):c.733G>A(p.Gly245Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000857 in 1,583,658 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G245G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0027 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 5 hom. )

Consequence

TICAM1
NM_182919.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -3.13

Publications

10 publications found

Variant links:

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

TICAM1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0037648976).

BP6

Variant 19-4817645-C-T is Benign according to our data. Variant chr19-4817645-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 473297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 2 AR,SD,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TICAM1	NM_182919.4 link	c.733G>A	p.Gly245Ser	missense_variant	Exon 2 of 2	ENST00000248244.6	NP_891549.1	Q8IUC6
TICAM1	NM_001385678.1 link	c.691G>A	p.Gly231Ser	missense_variant	Exon 3 of 3		NP_001372607.1
TICAM1	NM_001385679.1 link	c.598G>A	p.Gly200Ser	missense_variant	Exon 2 of 2		NP_001372608.1
TICAM1	NM_001385680.1 link	c.91G>A	p.Gly31Ser	missense_variant	Exon 3 of 3		NP_001372609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TICAM1	ENST00000248244.6 link	c.733G>A	p.Gly245Ser	missense_variant	Exon 2 of 2	1	NM_182919.4	ENSP00000248244.4		Q8IUC6

Frequencies

GnomAD3 genomes

AF:

0.00272

AC:

414

AN:

152088

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00657

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00557

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000603

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00110

AC:

245

AN:

222390

AF XY:

0.000948

show subpopulations

Gnomad AFR exome

AF:

0.00716

Gnomad AMR exome

AF:

0.00212

Gnomad ASJ exome

AF:

0.000134

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000388

Gnomad NFE exome

AF:

0.000506

Gnomad OTH exome

AF:

0.00149

GnomAD4 exome

AF:

0.000658

AC:

942

AN:

1431452

Hom.:

Cov.:

AF XY:

0.000639

AC XY:

453

AN XY:

709268

show subpopulations

African (AFR)

AF:

0.00684

AC:

225

AN:

32892

American (AMR)

AF:

0.00241

AC:

101

AN:

41824

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23884

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39456

South Asian (SAS)

AF:

0.0000489

AC:

AN:

81842

European-Finnish (FIN)

AF:

0.000319

AC:

AN:

50130

Middle Eastern (MID)

AF:

0.00356

AC:

AN:

5342

European-Non Finnish (NFE)

AF:

0.000448

AC:

491

AN:

1096960

Other (OTH)

AF:

0.00144

AC:

AN:

59122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

132

198

264

330

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00273

AC:

415

AN:

152206

Hom.:

Cov.:

AF XY:

0.00281

AC XY:

209

AN XY:

74424

show subpopulations

African (AFR)

AF:

0.00657

AC:

273

AN:

41528

American (AMR)

AF:

0.00557

AC:

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10614

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000603

AC:

AN:

68004

Other (OTH)

AF:

0.00568

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000947

Hom.:

Bravo

AF:

0.00316

ESP6500AA

AF:

0.00613

AC:

ESP6500EA

AF:

0.000815

AC:

ExAC

AF:

0.00105

AC:

127

ClinVar

Significance: Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TICAM1: BP4, BS2 -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Herpes simplex encephalitis, susceptibility to, 4

Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.68

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.0050

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.085

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.39

T;T

M_CAP

Benign

0.0074

MetaRNN

Benign

0.0038

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

N;.

PhyloP100

-3.1

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.020

N;.

REVEL

Benign

0.042

Sift

Benign

0.73

T;.

Sift4G

Benign

0.82

T;T

Polyphen

0.017

B;.

Vest4

0.086

MVP

0.22

MPC

0.22

ClinPred

0.0025

GERP RS

-5.1

Varity_R

0.021

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over