rs11466719

Positions:

• chr19-4818155-G-A
• chr19-4818155-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_182919.4(TICAM1):​c.223C>T​(p.Arg75Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00094 in 1,609,320 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R75S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0043 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (4 hom.)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.124

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0035818815).
• BP6: Variant 19-4818155-G-A is Benign according to our data. Variant chr19-4818155-G-A is described in ClinVar as [Benign]. Clinvar id is 540514.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000586 (854/1456982) while in subpopulation AFR AF= 0.0162 (542/33462). AF 95% confidence interval is 0.0151. There are 4 homozygotes in gnomad4_exome. There are 352 alleles in male gnomad4_exome subpopulation. Median coverage is 81. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TICAM1	NM_182919.4	c.223C>T	p.Arg75Cys	missense_variant	2/2	ENST00000248244.6
TICAM1	NM_001385678.1	c.181C>T	p.Arg61Cys	missense_variant	3/3
TICAM1	NM_001385679.1	c.88C>T	p.Arg30Cys	missense_variant	2/2
TICAM1	NM_001385680.1	c.-72+229C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TICAM1	ENST00000248244.6	c.223C>T	p.Arg75Cys	missense_variant	2/2	1	NM_182919.4	P1

Frequencies

GnomAD3 genomes AF: 0.00430 AC: 655 AN: 152220 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00112 AC: 267 AN: 238856 Hom.: 1 AF XY: 0.000864 AC XY: 113 AN XY: 130838

Gnomad AFR exome AF: 0.0154

Gnomad AMR exome AF: 0.000557

Gnomad ASJ exome AF: 0.000918

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000834

Gnomad OTH exome AF: 0.000340

GnomAD4 exome AF: 0.000586 AC: 854 AN: 1456982 Hom.: 4 Cov.: 81 AF XY: 0.000486 AC XY: 352 AN XY: 724994

Gnomad4 AFR exome AF: 0.0162

Gnomad4 AMR exome AF: 0.000583

Gnomad4 ASJ exome AF: 0.00123

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.00125

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152338 Hom.: 4 Cov.: 32 AF XY: 0.00443 AC XY: 330 AN XY: 74484

Gnomad4 AFR AF: 0.0151

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00117 Hom.: 37

Bravo AF: 0.00496

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0167 AC: 73

ESP6500EA AF: 0.000350 AC: 3

ExAC AF: 0.00134 AC: 162

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.0000594

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Herpes simplex encephalitis, susceptibility to, 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.047	N
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0036	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.031
Sift	Benign	0.090	T
Sift4G	Uncertain	0.014	D
Polyphen		0.013	B
Vest4		0.17
MVP		0.15
MPC		0.30
ClinPred		0.0086	T
GERP RS		0.96
Varity_R		0.17

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: rs11466719; hg19: chr19-4818167;