rs3923647

Positions:

• chr4-38797918-T-A
• chr4-38797918-T-C
• chr4-38797918-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003263.4(TLR1):​c.914A>T​(p.His305Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0276 in 1,614,120 control chromosomes in the GnomAD database, including 836 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.038 (161 hom., cov: 32)
  • Exomes 𝑓: 0.027 (675 hom.)
• Consequence: TLR1 NM_003263.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.91

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024781823).
• BP6: Variant 4-38797918-T-A is Benign according to our data. Variant chr4-38797918-T-A is described in ClinVar as [Benign]. Clinvar id is 3056910.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0707 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR1	NM_003263.4	c.914A>T	p.His305Leu	missense_variant	4/4	ENST00000308979.7	NP_003254.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR1	ENST00000308979.7	c.914A>T	p.His305Leu	missense_variant	4/4	1	NM_003263.4	ENSP00000354932	P1
TLR1	ENST00000502213.6	c.914A>T	p.His305Leu	missense_variant	3/3	1		ENSP00000421259	P1
TLR1	ENST00000505744.5	n.235+2939A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0382 AC: 5809 AN: 152174 Hom.: 161 Cov.: 32

Gnomad AFR AF: 0.0728

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.0292

Gnomad ASJ AF: 0.0576

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.00869

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0273

Gnomad OTH AF: 0.0425

GnomAD3 exomes AF: 0.0273 AC: 6835 AN: 250542 Hom.: 143 AF XY: 0.0262 AC XY: 3555 AN XY: 135576

Gnomad AFR exome AF: 0.0781

Gnomad AMR exome AF: 0.0170

Gnomad ASJ exome AF: 0.0663

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00902

Gnomad FIN exome AF: 0.0141

Gnomad NFE exome AF: 0.0317

Gnomad OTH exome AF: 0.0270

GnomAD4 exome AF: 0.0265 AC: 38768 AN: 1461828 Hom.: 675 Cov.: 36 AF XY: 0.0261 AC XY: 18965 AN XY: 727204

Gnomad4 AFR exome AF: 0.0737

Gnomad4 AMR exome AF: 0.0175

Gnomad4 ASJ exome AF: 0.0623

Gnomad4 EAS exome AF: 0.000176

Gnomad4 SAS exome AF: 0.00948

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.0273

Gnomad4 OTH exome AF: 0.0282

GnomAD4 genome AF: 0.0382 AC: 5819 AN: 152292 Hom.: 161 Cov.: 32 AF XY: 0.0367 AC XY: 2736 AN XY: 74488

Gnomad4 AFR AF: 0.0728

Gnomad4 AMR AF: 0.0291

Gnomad4 ASJ AF: 0.0576

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.0136

Gnomad4 NFE AF: 0.0273

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0192 Hom.: 8

Bravo AF: 0.0405

TwinsUK AF: 0.0294 AC: 109

ALSPAC AF: 0.0265 AC: 102

ESP6500AA AF: 0.0740 AC: 326

ESP6500EA AF: 0.0313 AC: 269

ExAC AF: 0.0295 AC: 3587

Asia WGS AF: 0.00693 AC: 25 AN: 3478

EpiCase AF: 0.0268

EpiControl AF: 0.0293

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

TLR1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.098
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.32
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.35	T;.
MetaRNN	Benign	0.0025	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.6	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Benign	0.079
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.035	D;D
Polyphen		0.017	B;B
Vest4		0.085
MPC		0.076
ClinPred		0.048	T
GERP RS		4.8
Varity_R		0.25
gMVP		0.43

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

Other links and lift over

dbSNP: rs3923647; hg19: chr4-38799539;