chr19-4817840-G-A

Position:

chr19-4817840-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_182919.4(TICAM1):c.538C>T(p.Arg180Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00114 in 1,610,864 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00085 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 2 hom. )

Consequence

TICAM1
NM_182919.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.333

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009036094).

BS2

High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
TICAM1	NM_182919.4 linkuse as main transcript	c.538C>T	p.Arg180Cys	missense_variant	2/2	ENST00000248244.6	NP_891549.1
TICAM1	NM_001385678.1 linkuse as main transcript	c.496C>T	p.Arg166Cys	missense_variant	3/3		NP_001372607.1
TICAM1	NM_001385679.1 linkuse as main transcript	c.403C>T	p.Arg135Cys	missense_variant	2/2		NP_001372608.1
TICAM1	NM_001385680.1 linkuse as main transcript	c.-71-34C>T		intron_variant			NP_001372609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICAM1	ENST00000248244.6 linkuse as main transcript	c.538C>T	p.Arg180Cys	missense_variant	2/2	1	NM_182919.4	ENSP00000248244	P1

Frequencies

GnomAD3 genomes

AF:

0.000854

AC:

130

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00135

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000934

AC:

230

AN:

246278

Hom.:

AF XY:

0.000959

AC XY:

128

AN XY:

133434

show subpopulations

Gnomad AFR exome

AF:

0.000370

Gnomad AMR exome

AF:

0.00145

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000503

Gnomad NFE exome

AF:

0.00146

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.00117

AC:

1710

AN:

1458552

Hom.:

Cov.:

AF XY:

0.00108

AC XY:

784

AN XY:

725412

show subpopulations

Gnomad4 AFR exome

AF:

0.000269

Gnomad4 AMR exome

AF:

0.00148

Gnomad4 ASJ exome

AF:

0.0000769

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000388

Gnomad4 NFE exome

AF:

0.00141

Gnomad4 OTH exome

AF:

0.00103

GnomAD4 genome

AF:

0.000854

AC:

130

AN:

152312

Hom.:

Cov.:

AF XY:

0.000725

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000265

Gnomad4 AMR

AF:

0.00118

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00135

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00125

Hom.:

Bravo

AF:

0.00114

TwinsUK

AF:

0.00189

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00256

AC:

ExAC

AF:

0.000889

AC:

108

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00115

EpiControl

AF:

0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Herpes simplex encephalitis, susceptibility to, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 25, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 180 of the TICAM1 protein (p.Arg180Cys). This variant is present in population databases (rs141394423, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with TICAM1-related conditions. ClinVar contains an entry for this variant (Variation ID: 540508). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

T;.

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.80

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.65

T;T

M_CAP

Benign

0.021

MetaRNN

Benign

0.0090

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.67

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.24

PROVEAN

Benign

-2.0

N;.

REVEL

Benign

0.093

Sift

Uncertain

0.0070

D;.

Sift4G

Uncertain

0.048

D;T

Polyphen

0.99

D;.

Vest4

0.071

MVP

0.10

MPC

0.30

ClinPred

0.027

GERP RS

-2.4

Varity_R

0.065

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over