rs5743618

chr4-38797027-C-Achr4-38797027-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.52 (27664 hom., cov: 32)
  • Exomes 𝑓: 0.35 (130576 hom.)
• Consequence: TLR1 NM_003263.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 0.245

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.5470836E-6).
• BP6: Variant 4-38797027-C-A is Benign according to our data. Variant chr4-38797027-C-A is described in ClinVar as [Benign]. Clinvar id is 8360.Status of the report is criteria_provided_single_submitter, 1 stars.
• 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/exons	MANE	UniProt
TLR1	NM_003263.4	c.1805G>T	p.Ser602Ile	missense_variant	4/4	ENST00000308979.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR1	ENST00000308979.7	c.1805G>T	p.Ser602Ile	missense_variant	4/4	1	NM_003263.4	P1
TLR1	ENST00000502213.6	c.1805G>T	p.Ser602Ile	missense_variant	3/3	1		P1
TLR1	ENST00000505744.5	n.235+3830G>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79419 AN: 151982 Hom.: 27592 Cov.: 32

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

GnomAD3 exomes AF: 0.529 AC: 132776 AN: 251036 Hom.: 46587 AF XY: 0.530 AC XY: 71913 AN XY: 135698

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 SAS exome AF: 0.896

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.: 48 AF XY: 0.364 AC XY: 264348 AN XY: 727154

Gnomad4 AFR exome AF: 0.888

Gnomad4 AMR exome AF: 0.762

Gnomad4 ASJ exome AF: 0.525

Gnomad4 EAS exome AF: 0.989

Gnomad4 SAS exome AF: 0.893

Gnomad4 FIN exome AF: 0.146

Gnomad4 NFE exome AF: 0.248

Gnomad4 OTH exome AF: 0.432

GnomAD4 genome AF: 0.523 AC: 79556 AN: 152102 Hom.: 27664 Cov.: 32 AF XY: 0.531 AC XY: 39486 AN XY: 74366

Gnomad4 AFR AF: 0.868

Gnomad4 AMR AF: 0.680

Gnomad4 ASJ AF: 0.538

Gnomad4 EAS AF: 0.988

Gnomad4 SAS AF: 0.906

Gnomad4 FIN AF: 0.131

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.597

Alfa AF: 0.404 Hom.: 3210

Bravo AF: 0.573

ESP6500AA AF: 0.850 AC: 3744

ESP6500EA AF: 0.288 AC: 2480

ExAC AF: 0.539 AC: 65450

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Leprosy, protection against Benign:1

protective, no assertion criteria provided

literature only

OMIM

Dec 01, 2012

- -

TLR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

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

Uncertain risk allele, no assertion criteria provided

case-control

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

Jun 10, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.81	T
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	N
LIST_S2	Benign	0.054	T;.
MetaRNN	Benign	0.0000015	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.5	N;N
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.28	T
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	T
GERP RS		2.8
Varity_R		0.053
gMVP		0.19

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

Other links and lift over

dbSNP: rs5743618; hg19: chr4-38798648; COSMIC: COSV58304302; COSMIC: COSV58304302;