rs5743618

Variant names:

• chr4-38797027-C-A
• rs5743618
• NM_003263.4:c.1805G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-38797027-C-A
• chr4-38797027-C-G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 15/21 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
• Clinical Significance: Conflicting classifications of pathogenicity; protective no assertion criteria provided B:2 O:1
• Conservation: PhyloP100: 0.245
• Publications: 272 publications found

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

Our verdict: Benign. The variant received -13 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 Conflicting_classifications_of_pathogenicity|protective. ClinVar VariationId is 8360.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.966 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR1	NM_003263.4	MANE Select	c.1805G>T	p.Ser602Ile	missense	Exon 4 of 4	NP_003254.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR1	ENST00000308979.7	TSL:1 MANE Select	c.1805G>T	p.Ser602Ile	missense	Exon 4 of 4	ENSP00000354932.2	Q15399
	TLR1	ENST00000502213.7	TSL:1	c.1805G>T	p.Ser602Ile	missense	Exon 4 of 4	ENSP00000421259.1	Q15399
	TLR1	ENST00000862584.1		c.1805G>T	p.Ser602Ile	missense	Exon 4 of 4	ENSP00000532643.1

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

GnomAD2 exomes AF: 0.529 AC: 132776 AN: 251036 AF XY: 0.530

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

African (AFR) AF: 0.888 AC: 29725 AN: 33468

American (AMR) AF: 0.762 AC: 34071 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.525 AC: 13715 AN: 26136

East Asian (EAS) AF: 0.989 AC: 39268 AN: 39700

South Asian (SAS) AF: 0.893 AC: 76984 AN: 86256

European-Finnish (FIN) AF: 0.146 AC: 7774 AN: 53420

Middle Eastern (MID) AF: 0.795 AC: 4588 AN: 5768

European-Non Finnish (NFE) AF: 0.248 AC: 276189 AN: 1111880

Other (OTH) AF: 0.432 AC: 26092 AN: 60386

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

African (AFR) AF: 0.868 AC: 35990 AN: 41464

American (AMR) AF: 0.680 AC: 10387 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 1865 AN: 3468

East Asian (EAS) AF: 0.988 AC: 5117 AN: 5178

South Asian (SAS) AF: 0.906 AC: 4369 AN: 4822

European-Finnish (FIN) AF: 0.131 AC: 1386 AN: 10590

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18642 AN: 67976

Other (OTH) AF: 0.597 AC: 1262 AN: 2114

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity; protective

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Leprosy, susceptibility to, 1 (1)
-	-	1	TLR1-related disorder (1)
-	-	-	Leprosy, protection against (1)

Computational scores

Source: dbNSFP v4.9

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
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
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-2.5	N
PhyloP100		0.24
PrimateAI	Benign	0.28	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.056
Sift	Benign	1.0	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.073
ClinPred		0.0037	T
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

Other links and lift over

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