rs143066432

Variant names:

• chr19-4816709-C-G
• NM_182919.4:c.1669G>C

Your query was ambiguous. Multiple possible variants found:

• chr19-4816709-C-G
• chr19-4816709-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_182919.4(TICAM1):​c.1669G>C​(p.Asp557His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. D557D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TICAM1 NM_182919.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.50

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15025279).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TICAM1	NM_182919.4	c.1669G>C	p.Asp557His	missense_variant	Exon 2 of 2	ENST00000248244.6	NP_891549.1
TICAM1	NM_001385678.1	c.1627G>C	p.Asp543His	missense_variant	Exon 3 of 3		NP_001372607.1
TICAM1	NM_001385679.1	c.1534G>C	p.Asp512His	missense_variant	Exon 2 of 2		NP_001372608.1
TICAM1	NM_001385680.1	c.1027G>C	p.Asp343His	missense_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.1669G>C	p.Asp557His	missense_variant	Exon 2 of 2	1	NM_182919.4	ENSP00000248244.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 62

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 24, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1669G>C (p.D557H) alteration is located in exon 2 (coding exon 1) of the TICAM1 gene. This alteration results from a G to C substitution at nucleotide position 1669, causing the aspartic acid (D) at amino acid position 557 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.15	T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.2	L;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.088
Sift	Uncertain	0.019	D;.
Sift4G	Uncertain	0.031	D;D
Polyphen		0.70	P;.
Vest4		0.24
MutPred		0.12		Gain of MoRF binding (P = 0.05);.;
MVP		0.14
MPC		0.56
ClinPred		0.36	T
GERP RS		0.86
Varity_R		0.070

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-4816721;