19-4816229-G-T

Variant names:

• chr19-4816229-G-T
• rs1046673
• NM_182919.4:c.*10C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_182919.4(TICAM1):​c.*10C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000741 in 1,349,998 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.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.4e-7 (0 hom.)
• Consequence: TICAM1 NM_182919.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.340
• 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TICAM1	NM_182919.4	c.*10C>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000248244.6	NP_891549.1
TICAM1	NM_001385678.1	c.*10C>A		3_prime_UTR_variant	Exon 3 of 3		NP_001372607.1
TICAM1	NM_001385679.1	c.*10C>A		3_prime_UTR_variant	Exon 2 of 2		NP_001372608.1
TICAM1	NM_001385680.1	c.*10C>A		3_prime_UTR_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.*10C>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_182919.4	ENSP00000248244.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.41e-7 AC: 1 AN: 1349998 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 660386

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30004

American (AMR) AF: 0.00 AC: 0 AN: 28202

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19718

East Asian (EAS) AF: 0.00 AC: 0 AN: 38394

South Asian (SAS) AF: 0.00 AC: 0 AN: 69172

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4402

European-Non Finnish (NFE) AF: 9.42e-7 AC: 1 AN: 1061416

Other (OTH) AF: 0.00 AC: 0 AN: 55620

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.7
DANN	Benign	0.58
PhyloP100		0.34

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: rs1046673; hg19: chr19-4816241;