chr4-38797027-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003263.4(TLR1):c.1805G>T(p.Ser602Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.364 in 1,613,828 control chromosomes in the GnomAD database, including 158,240 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity,protective (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S602G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.52 ( 27664 hom., cov: 32)

Exomes 𝑓: 0.35 ( 130576 hom. )

Consequence

TLR1
NM_003263.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity; protective no assertion criteria provided B:2O:1

Conservation

PhyloP100: 0.245

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.5470836E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR1	NM_003263.4 link	c.1805G>T	p.Ser602Ile	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.1805G>T	p.Ser602Ile	missense_variant	Exon 4 of 4	1	NM_003263.4	ENSP00000354932.2	Q15399
TLR1	ENST00000502213.6 link	c.1805G>T	p.Ser602Ile	missense_variant	Exon 3 of 3	1		ENSP00000421259.1	Q15399
TLR1	ENST00000505744.5 link	n.235+3830G>T		intron_variant	Intron 3 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.523

AC:

79419

AN:

151982

Hom.:

27592

Cov.:

show subpopulations

Gnomad AFR

AF:

0.868

Gnomad AMI

AF:

0.337

Gnomad AMR

AF:

0.679

Gnomad ASJ

AF:

0.538

Gnomad EAS

AF:

0.988

Gnomad SAS

AF:

0.906

Gnomad FIN

AF:

0.131

Gnomad MID

AF:

0.778

Gnomad NFE

AF:

0.274

Gnomad OTH

AF:

0.592

GnomAD2 exomes

AF:

0.529

AC:

132776

AN:

251036

AF XY:

0.530

show subpopulations

Gnomad AFR exome

AF:

0.881

Gnomad AMR exome

AF:

0.773

Gnomad ASJ exome

AF:

0.524

Gnomad EAS exome

AF:

0.989

Gnomad FIN exome

AF:

0.138

Gnomad NFE exome

AF:

0.308

Gnomad OTH exome

AF:

0.488

GnomAD4 exome

AF:

0.348

AC:

508406

AN:

1461726

Hom.:

130576

Cov.:

AF XY:

0.364

AC XY:

264348

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.888

AC:

29725

AN:

33468

Gnomad4 AMR exome

AF:

0.762

AC:

34071

AN:

44712

Gnomad4 ASJ exome

AF:

0.525

AC:

13715

AN:

26136

Gnomad4 EAS exome

AF:

0.989

AC:

39268

AN:

39700

Gnomad4 SAS exome

AF:

0.893

AC:

76984

AN:

86256

Gnomad4 FIN exome

AF:

0.146

AC:

7774

AN:

53420

Gnomad4 NFE exome

AF:

0.248

AC:

276189

AN:

1111880

Gnomad4 Remaining exome

AF:

0.432

AC:

26092

AN:

60386

Heterozygous variant carriers

12930

25860

38789

51719

64649

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Exome Hom

Variant carriers

9678

19356

29034

38712

48390

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.523

AC:

79556

AN:

152102

Hom.:

27664

Cov.:

AF XY:

0.531

AC XY:

39486

AN XY:

74366

show subpopulations

Gnomad4 AFR

AF:

0.868

AC:

0.867982

AN:

0.867982

Gnomad4 AMR

AF:

0.680

AC:

0.679511

AN:

0.679511

Gnomad4 ASJ

AF:

0.538

AC:

0.537774

AN:

0.537774

Gnomad4 EAS

AF:

0.988

AC:

0.988219

AN:

0.988219

Gnomad4 SAS

AF:

0.906

AC:

0.906056

AN:

0.906056

Gnomad4 FIN

AF:

0.131

AC:

0.130878

AN:

0.130878

Gnomad4 NFE

AF:

0.274

AC:

0.274244

AN:

0.274244

Gnomad4 OTH

AF:

0.597

AC:

0.596973

AN:

0.596973

Heterozygous variant carriers

1216

2432

3647

4863

6079

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Genome Hom

Variant carriers

622

1244

1866

2488

3110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.439

Hom.:

7011

Bravo

AF:

0.573

ESP6500AA

AF:

0.850

AC:

3744

ESP6500EA

AF:

0.288

AC:

2480

ExAC

AF:

0.539

AC:

65450

ClinVar

Significance: Conflicting classifications of pathogenicity; protective

Submissions summary: Benign:2Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Leprosy, protection against

Benign:1

Dec 01, 2012

OMIM

Significance:protective

Review Status:no assertion criteria provided

Collection Method:literature only

- -

TLR1-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Leprosy, susceptibility to, 1

Other:1

Jun 10, 2022

Centro Dermatológico Federico Lleras Acosta, Hospital Universitario Centro Dermatológico Federico Lleras Acosta

Significance:Uncertain risk allele

Review Status:no assertion criteria provided

Collection Method:case-control

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.81

BayesDel_noAF

Benign

-0.79

CADD

Benign

6.0

DANN

Benign

0.11

DEOGEN2

Benign

0.049

T;T

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.042

LIST_S2

Benign

0.054

T;.

MetaRNN

Benign

0.0000015

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-2.5

N;N

PrimateAI

Benign

0.28

PROVEAN

Benign

2.3

N;N

REVEL

Benign

0.056

Sift

Benign

1.0

T;T

Sift4G

Benign

0.60

T;T

Polyphen

0.0

B;B

Vest4

0.015

MPC

0.073

ClinPred

0.0037

GERP RS

2.8

Varity_R

0.053

gMVP

0.19

Mutation Taster

=99/1

polymorphism (auto)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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