chr19-4818283-G-A

Position:

• chr19-4818283-G-A

Variant summary

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

The ENST00000248244.6(TICAM1):​c.95C>T​(p.Thr32Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00146 in 1,612,904 control chromosomes in the GnomAD database, including 50 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 (★).

• Frequency:
  • Genomes: 𝑓 0.0014 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (48 hom.)
• Consequence: TICAM1 ENST00000248244.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0660

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=0.0027892292).
• BP6: Variant 19-4818283-G-A is Benign according to our data. Variant chr19-4818283-G-A is described in ClinVar as [Benign]. Clinvar id is 540521.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00141 (215/152320) while in subpopulation EAS AF= 0.0357 (185/5182). AF 95% confidence interval is 0.0315. There are 2 homozygotes in gnomad4. There are 129 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TICAM1	NM_182919.4	c.95C>T	p.Thr32Ile	missense_variant	2/2	ENST00000248244.6	NP_891549.1
TICAM1	NM_001385678.1	c.53C>T	p.Thr18Ile	missense_variant	3/3		NP_001372607.1
TICAM1	NM_001385679.1	c.-41C>T		5_prime_UTR_variant	2/2		NP_001372608.1
TICAM1	NM_001385680.1	c.-72+101C>T		intron_variant			NP_001372609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TICAM1	ENST00000248244.6	c.95C>T	p.Thr32Ile	missense_variant	2/2	1	NM_182919.4	ENSP00000248244	P1

Frequencies

GnomAD3 genomes AF: 0.00142 AC: 216 AN: 152202 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0358

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00313 AC: 780 AN: 249220 Hom.: 9 AF XY: 0.00293 AC XY: 396 AN XY: 135086

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.0372

Gnomad SAS exome AF: 0.00127

Gnomad FIN exome AF: 0.0000972

Gnomad NFE exome AF: 0.000337

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.00147 AC: 2144 AN: 1460584 Hom.: 48 Cov.: 80 AF XY: 0.00147 AC XY: 1066 AN XY: 726620

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.0423

Gnomad4 SAS exome AF: 0.00153

Gnomad4 FIN exome AF: 0.000115

Gnomad4 NFE exome AF: 0.000160

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152320 Hom.: 2 Cov.: 32 AF XY: 0.00173 AC XY: 129 AN XY: 74484

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.0357

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00173 Hom.: 4

Bravo AF: 0.00181

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00299 AC: 363

Asia WGS AF: 0.0150 AC: 52 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000356

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

Labcorp Genetics (formerly Invitae), Labcorp

Jan 09, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.67
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.041
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.043	D
Polyphen		0.92	P
Vest4		0.27
MVP		0.11
MPC		0.47
ClinPred		0.026	T
GERP RS		-0.46
Varity_R		0.11

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: rs79591246; hg19: chr19-4818295; COSMIC: COSV50230355; COSMIC: COSV50230355;