19-4816278-C-A

Variant names:

• chr19-4816278-C-A
• rs748477430
• NM_182919.4:c.2100G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_182919.4(TICAM1):​c.2100G>T​(p.Gly700Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000733 in 1,363,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G700G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: TICAM1 NM_182919.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.870
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP7: Synonymous conserved (PhyloP=-0.87 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TICAM1	NM_182919.4	c.2100G>T	p.Gly700Gly	synonymous_variant	Exon 2 of 2	ENST00000248244.6	NP_891549.1
TICAM1	NM_001385678.1	c.2058G>T	p.Gly686Gly	synonymous_variant	Exon 3 of 3		NP_001372607.1
TICAM1	NM_001385679.1	c.1965G>T	p.Gly655Gly	synonymous_variant	Exon 2 of 2		NP_001372608.1
TICAM1	NM_001385680.1	c.1458G>T	p.Gly486Gly	synonymous_variant	Exon 3 of 3		NP_001372609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TICAM1	ENST00000248244.6	c.2100G>T	p.Gly700Gly	synonymous_variant	Exon 2 of 2	1	NM_182919.4	ENSP00000248244.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.33e-7 AC: 1 AN: 1363666 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 667808

African (AFR) AF: 0.00 AC: 0 AN: 30180

American (AMR) AF: 0.00 AC: 0 AN: 28934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19980

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38718

South Asian (SAS) AF: 0.00 AC: 0 AN: 70584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48796

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5208

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1065196

Other (OTH) AF: 0.00 AC: 0 AN: 56070

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.2
DANN	Benign	0.84
PhyloP100		-0.87

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

Other links and lift over

dbSNP: rs748477430; hg19: chr19-4816290;