4-153703296-A-G

Variant names:

• chr4-153703296-A-G
• rs1001189972
• NM_001318789.2:c.389A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001318789.2(TLR2):​c.389A>G​(p.Asn130Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: TLR2 NM_001318789.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.55

Genes affected

TLR2 (HGNC:11848): (toll like receptor 2) The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans and share structural and functional similarities. This protein is a cell-surface protein that can form heterodimers with other TLR family members to recognize conserved molecules derived from microorganisms known as pathogen-associated molecular patterns (PAMPs). Activation of TLRs by PAMPs leads to an up-regulation of signaling pathways to modulate the host's inflammatory response. This gene is also thought to promote apoptosis in response to bacterial lipoproteins. This gene has been implicated in the pathogenesis of several autoimmune diseases. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38358396).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR2	NM_001318789.2	c.389A>G	p.Asn130Ser	missense_variant	Exon 3 of 3	ENST00000642700.2	NP_001305718.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR2	ENST00000642700.2	c.389A>G	p.Asn130Ser	missense_variant	Exon 3 of 3		NM_001318789.2	ENSP00000494425.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.389A>G (p.N130S) alteration is located in exon 3 (coding exon 1) of the TLR2 gene. This alteration results from a A to G substitution at nucleotide position 389, causing the asparagine (N) at amino acid position 130 to be replaced by a serine (S). 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	0.16
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	.;T;T;T;T
Eigen	Benign	-0.062
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;.;.;.;D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.38	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Pathogenic	2.9	.;M;M;M;M
PrimateAI	Benign	0.32	T
PROVEAN	Uncertain	-3.4	.;.;.;.;D
REVEL	Benign	0.14
Sift	Uncertain	0.024	.;.;.;.;D
Sift4G	Uncertain	0.026	.;.;.;.;D
Polyphen		0.15	.;B;B;B;B
Vest4		0.14
MutPred		0.70		Gain of disorder (P = 0.0679);Gain of disorder (P = 0.0679);Gain of disorder (P = 0.0679);Gain of disorder (P = 0.0679);Gain of disorder (P = 0.0679);
MVP		0.53
MPC		0.073
ClinPred		0.87	D
GERP RS		4.5
Varity_R		0.54
gMVP		0.43

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: rs1001189972; hg19: chr4-154624448;