chr4-153703287-C-A

Variant names:

• chr4-153703287-C-A
• NM_001318789.2:c.380C>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001318789.2(TLR2):​c.380C>A​(p.Thr127Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TLR2 NM_001318789.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.355

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02447766).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR2	NM_001318789.2	c.380C>A	p.Thr127Lys	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.380C>A	p.Thr127Lys	missense_variant	Exon 3 of 3		NM_001318789.2	ENSP00000494425.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459374 Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1 AN XY: 725932

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.050
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.042
DANN	Benign	0.15
DEOGEN2	Benign	0.052	.;T;T;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.0040	N
LIST_S2	Benign	0.63	T;.;.;.;T
M_CAP	Benign	0.0026	T
MetaRNN	Benign	0.024	T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-2.7	.;N;N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	2.5	.;.;.;.;N
REVEL	Benign	0.021
Sift	Benign	1.0	.;.;.;.;T
Sift4G	Benign	1.0	.;.;.;.;T
Polyphen		0.0	.;B;B;B;B
Vest4		0.049
MutPred		0.57		Gain of ubiquitination at T127 (P = 0.0408);Gain of ubiquitination at T127 (P = 0.0408);Gain of ubiquitination at T127 (P = 0.0408);Gain of ubiquitination at T127 (P = 0.0408);Gain of ubiquitination at T127 (P = 0.0408);
MVP		0.29
MPC		0.078
ClinPred		0.066	T
GERP RS		-3.3
Varity_R		0.11
gMVP		0.31

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: chr4-154624439;