19-4816357-G-A

Position:

chr19-4816357-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_182919.4(TICAM1):c.2021C>T(p.Pro674Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000315 in 1,587,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TICAM1
NM_182919.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.81

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 Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06615016).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TICAM1	NM_182919.4 linkuse as main transcript	c.2021C>T	p.Pro674Leu	missense_variant	2/2	ENST00000248244.6
TICAM1	NM_001385678.1 linkuse as main transcript	c.1979C>T	p.Pro660Leu	missense_variant	3/3
TICAM1	NM_001385679.1 linkuse as main transcript	c.1886C>T	p.Pro629Leu	missense_variant	2/2
TICAM1	NM_001385680.1 linkuse as main transcript	c.1379C>T	p.Pro460Leu	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICAM1	ENST00000248244.6 linkuse as main transcript	c.2021C>T	p.Pro674Leu	missense_variant	2/2	1	NM_182919.4	P1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000177

AC:

AN:

226220

Hom.:

AF XY:

0.00000821

AC XY:

AN XY:

121772

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000230

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000139

AC:

AN:

1435548

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

712442

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000506

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152320

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 4

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 23, 2018

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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with TICAM1-related disease. This variant is present in population databases (rs536690750, ExAC 0.03%). This sequence change replaces proline with leucine at codon 674 of the TICAM1 protein (p.Pro674Leu). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and leucine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

T;.

Eigen

Benign

-0.061

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.30

LIST_S2

Benign

0.67

T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.066

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.97

L;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.8

D;.

REVEL

Benign

0.073

Sift

Uncertain

0.0030

D;.

Sift4G

Uncertain

0.0060

D;D

Polyphen

0.95

P;.

Vest4

0.32

MutPred

0.35

Loss of glycosylation at P674 (P = 0.0075);.;

MVP

0.16

MPC

0.79

ClinPred

0.59

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

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