chr19-4816449-C-G

Variant names:

• chr19-4816449-C-G
• rs201978370
• NM_182919.4:c.1929G>C

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_182919.4(TICAM1):​c.1929G>C​(p.Pro643Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Synonymous variant affecting the same amino acid position (i.e. P643P) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TICAM1 NM_182919.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.75
• 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, AD, SD Classification: STRONG, LIMITED Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 19-4816449-C-G is Benign according to our data. Variant chr19-4816449-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2008428.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.75 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_182919.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICAM1	NM_182919.4	MANE Select	c.1929G>C	p.Pro643Pro	synonymous	Exon 2 of 2	NP_891549.1	Q8IUC6
	TICAM1	NM_001385678.1		c.1887G>C	p.Pro629Pro	synonymous	Exon 3 of 3	NP_001372607.1
	TICAM1	NM_001385679.1		c.1794G>C	p.Pro598Pro	synonymous	Exon 2 of 2	NP_001372608.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TICAM1	ENST00000248244.6	TSL:1 MANE Select	c.1929G>C	p.Pro643Pro	synonymous	Exon 2 of 2	ENSP00000248244.4	Q8IUC6
	TICAM1	ENST00000868535.1		c.1929G>C	p.Pro643Pro	synonymous	Exon 3 of 3	ENSP00000538594.1

Frequencies

GnomAD3 genomes AF: 0.0000151 AC: 2 AN: 132088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000781

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000161

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1170942 Hom.: 0 Cov.: 42 AF XY: 0.00 AC XY: 0 AN XY: 574564

African (AFR) AF: 0.00 AC: 0 AN: 24898

American (AMR) AF: 0.00 AC: 0 AN: 29200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13282

East Asian (EAS) AF: 0.00 AC: 0 AN: 18872

South Asian (SAS) AF: 0.00 AC: 0 AN: 74468

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29006

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 934948

Other (OTH) AF: 0.00 AC: 0 AN: 42510

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000151 AC: 2 AN: 132154 Hom.: 0 Cov.: 32 AF XY: 0.0000156 AC XY: 1 AN XY: 63900

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

African (AFR) AF: 0.00 AC: 0 AN: 35368

American (AMR) AF: 0.0000779 AC: 1 AN: 12834

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3224

East Asian (EAS) AF: 0.00 AC: 0 AN: 3998

South Asian (SAS) AF: 0.00 AC: 0 AN: 3726

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8018

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.0000161 AC: 1 AN: 62064

Other (OTH) AF: 0.00 AC: 0 AN: 1830

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000812204), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Herpes simplex encephalitis, susceptibility to, 4 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.022
DANN	Benign	0.38
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism

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: rs201978370; hg19: chr19-4816461;