4-38796796-A-G

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PP3PP5BP4BS2_Supporting

The NM_003263.4(TLR1):c.2036T>C(p.Ile679Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000637 in 1,614,210 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 15 hom. )

Consequence

TLR1
NM_003263.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.32

Variant links:

Genes affected

TLR1 (HGNC:11847): (toll like receptor 1) 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. They recognize pathogen-associated molecular patterns (PAMPs) that are expressed on infectious agents, and mediate the production of cytokines necessary for the development of effective immunity. The various TLRs exhibit different patterns of expression. This gene is ubiquitously expressed, and at higher levels than other TLR genes. Different length transcripts presumably resulting from use of alternative polyadenylation site, and/or from alternative splicing, have been noted for this gene. [provided by RefSeq, Jul 2008]

TLR1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_noAF, Cadd, Eigen, FATHMM_MKL, MutationAssessor, phyloP100way_vertebrate, PROVEAN [when BayesDel_addAF, max_spliceai, M_CAP, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 4-38796796-A-G is Pathogenic according to our data. Variant chr4-38796796-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 983492.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.011945665). . Strength limited to SUPPORTING due to the PP5.

BS2

High AC in GnomAd4 at 62 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR1	NM_003263.4 link	c.2036T>C	p.Ile679Thr	missense_variant	Exon 4 of 4	ENST00000308979.7	NP_003254.2	Q15399

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TLR1	ENST00000308979.7 link	c.2036T>C	p.Ile679Thr	missense_variant	Exon 4 of 4	1	NM_003263.4	ENSP00000354932.2	Q15399
TLR1	ENST00000502213.6 link	c.2036T>C	p.Ile679Thr	missense_variant	Exon 3 of 3	1		ENSP00000421259.1	Q15399
TLR1	ENST00000505744.5 link	n.235+4061T>C		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152204

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00117

AC:

293

AN:

251414

Hom.:

AF XY:

0.00162

AC XY:

220

AN XY:

135868

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00924

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000792

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000661

AC:

967

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000950

AC XY:

691

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000176

Gnomad4 SAS exome

AF:

0.00991

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000620

Gnomad4 OTH exome

AF:

0.000447

GnomAD4 genome

AF:

0.000407

AC:

AN:

152322

Hom.:

Cov.:

AF XY:

0.000631

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0116

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000809

Hom.:

Bravo

AF:

0.000117

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00128

AC:

155

EpiCase

AF:

0.000273

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Rheumatoid arthritis

Pathogenic:1

Nov 02, 2020

Institute of Biochemistry and Biotechnology, Faculty of Life Sciences, University of the Punjab

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

Mutations in TLR1 gene might disrugulate the inflammatory mechanism invloved in rhumatoid arthritis -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;.

M_CAP

Benign

0.034

MetaRNN

Benign

0.012

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Pathogenic

3.9

H;H

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-4.5

D;D

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.86

MVP

0.58

MPC

0.40

ClinPred

0.29

GERP RS

5.3

Varity_R

0.95

gMVP

0.14

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over