rs4833095

Positions:

• chr4-38798089-T-C

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.743A>G​(p.Asn248Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,613,238 control chromosomes in the GnomAD database, including 90,036 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.44 (19255 hom., cov: 32)
  • Exomes 𝑓: 0.27 (70781 hom.)
• Consequence: TLR1 NM_003263.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1 O:1
• Conservation: PhyloP100: -0.964

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=2.6334178E-6).
• BP6: Variant 4-38798089-T-C is Benign according to our data. Variant chr4-38798089-T-C is described in ClinVar as [Benign]. Clinvar id is 8361.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR1	NM_003263.4	c.743A>G	p.Asn248Ser	missense_variant	4/4	ENST00000308979.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR1	ENST00000308979.7	c.743A>G	p.Asn248Ser	missense_variant	4/4	1	NM_003263.4	P1
TLR1	ENST00000502213.6	c.743A>G	p.Asn248Ser	missense_variant	3/3	1		P1
TLR1	ENST00000505744.5	n.235+2768A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66260 AN: 152006 Hom.: 19203 Cov.: 32

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.483

GnomAD3 exomes AF: 0.381 AC: 95308 AN: 250080 Hom.: 22422 AF XY: 0.374 AC XY: 50670 AN XY: 135426

Gnomad AFR exome AF: 0.801

Gnomad AMR exome AF: 0.517

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.595

Gnomad SAS exome AF: 0.486

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.273 AC: 399521 AN: 1461114 Hom.: 70781 Cov.: 36 AF XY: 0.279 AC XY: 202717 AN XY: 726712

Gnomad4 AFR exome AF: 0.808

Gnomad4 AMR exome AF: 0.513

Gnomad4 ASJ exome AF: 0.412

Gnomad4 EAS exome AF: 0.634

Gnomad4 SAS exome AF: 0.481

Gnomad4 FIN exome AF: 0.124

Gnomad4 NFE exome AF: 0.218

Gnomad4 OTH exome AF: 0.329

GnomAD4 genome AF: 0.436 AC: 66372 AN: 152124 Hom.: 19255 Cov.: 32 AF XY: 0.435 AC XY: 32398 AN XY: 74396

Gnomad4 AFR AF: 0.791

Gnomad4 AMR AF: 0.503

Gnomad4 ASJ AF: 0.418

Gnomad4 EAS AF: 0.597

Gnomad4 SAS AF: 0.490

Gnomad4 FIN AF: 0.114

Gnomad4 NFE AF: 0.239

Gnomad4 OTH AF: 0.486

Alfa AF: 0.316 Hom.: 16136

Bravo AF: 0.480

TwinsUK AF: 0.226 AC: 837

ALSPAC AF: 0.248 AC: 954

ESP6500AA AF: 0.777 AC: 3424

ESP6500EA AF: 0.249 AC: 2141

ExAC AF: 0.393 AC: 47671

Asia WGS AF: 0.564 AC: 1960 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

TLR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 18, 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, 5 Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Jun 15, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.27
DANN	Benign	0.43
DEOGEN2	Benign	0.24	T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.060	T;.
MetaRNN	Benign	0.0000026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.028
Sift	Benign	0.17	T;T
Sift4G	Benign	0.25	T;T
Polyphen		0.0010	B;B
Vest4		0.016
MPC		0.053
ClinPred		0.0096	T
GERP RS		-3.2
Varity_R		0.11
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

Other links and lift over

dbSNP: rs4833095; hg19: chr4-38799710; COSMIC: COSV58303357; COSMIC: COSV58303357;