rs5030719

Variant names:

• chr9-117713658-G-T
• rs5030719
• NM_138554.5:c.1530G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-117713658-G-T
• chr9-117713658-G-A
• chr9-117713658-G-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_138554.5(TLR4):​c.1530G>T​(p.Gln510His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00145 in 1,614,044 control chromosomes in the GnomAD database, including 27 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 Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0073 (16 hom., cov: 32)
  • Exomes 𝑓: 0.00084 (11 hom.)
• Consequence: TLR4 NM_138554.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.482
• Publications: 26 publications found

Genes affected

TLR4 (HGNC:11850): (toll like receptor 4) 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 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. In silico studies have found a particularly strong binding of surface TLR4 with the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus disease-2019 (COVID-19). This receptor has also been implicated in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations in this gene have been associated with differences in LPS responsiveness, and with susceptibility to age-related macular degeneration. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2020]

TLR4 Gene-Disease associations (from GenCC):

• inflammatory bowel disease

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

ENSG00000285082 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002524972).
• BP6: Variant 9-117713658-G-T is Benign according to our data. Variant chr9-117713658-G-T is described in ClinVar as Benign. ClinVar VariationId is 3039260.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00734 (1117/152282) while in subpopulation AFR AF = 0.0252 (1047/41546). AF 95% confidence interval is 0.0239. There are 16 homozygotes in GnomAd4. There are 522 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 16 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138554.5. 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
	TLR4	NM_138554.5	MANE Select	c.1530G>T	p.Gln510His	missense	Exon 3 of 3	NP_612564.1	O00206-1
	TLR4	NM_003266.4		c.1410G>T	p.Gln470His	missense	Exon 4 of 4	NP_003257.1	O00206-2
	TLR4	NM_138557.3		c.930G>T	p.Gln310His	missense	Exon 2 of 2	NP_612567.1	O00206-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000355622.8	TSL:1 MANE Select	c.1530G>T	p.Gln510His	missense	Exon 3 of 3	ENSP00000363089.5	O00206-1
	TLR4	ENST00000394487.5	TSL:1	c.1410G>T	p.Gln470His	missense	Exon 4 of 4	ENSP00000377997.4	O00206-2
	TLR4	ENST00000472304.2	TSL:1	c.*1264G>T		3_prime_UTR	Exon 2 of 2	ENSP00000496429.1	A0A2R8Y7P4

Frequencies

GnomAD3 genomes AF: 0.00734 AC: 1117 AN: 152164 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00812

GnomAD2 exomes AF: 0.00207 AC: 519 AN: 251040 AF XY: 0.00151

Gnomad AFR exome AF: 0.0253

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.000841 AC: 1229 AN: 1461762 Hom.: 11 Cov.: 32 AF XY: 0.000723 AC XY: 526 AN XY: 727176

African (AFR) AF: 0.0269 AC: 900 AN: 33474

American (AMR) AF: 0.00246 AC: 110 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53350

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000683 AC: 76 AN: 1111990

Other (OTH) AF: 0.00214 AC: 129 AN: 60392

GnomAD4 genome AF: 0.00734 AC: 1117 AN: 152282 Hom.: 16 Cov.: 32 AF XY: 0.00701 AC XY: 522 AN XY: 74454

African (AFR) AF: 0.0252 AC: 1047 AN: 41546

American (AMR) AF: 0.00294 AC: 45 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68032

Other (OTH) AF: 0.00803 AC: 17 AN: 2116

Alfa AF: 0.00267 Hom.: 13

Bravo AF: 0.00794

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00254 AC: 309

Asia WGS AF: 0.00202 AC: 7 AN: 3476

EpiCase AF: 0.000218

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	TLR4-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.15
DANN	Benign	0.70
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.70	N
PhyloP100		-0.48
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.0080
Sift	Benign	0.24	T
Sift4G	Benign	0.32	T
Polyphen		0.0030	B
Vest4		0.062
MutPred		0.25		Loss of helix (P = 0.0558)
MVP		0.21
MPC		0.084
ClinPred		0.0037	T
GERP RS		-1.6
Varity_R		0.26
gMVP		0.19
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs5030719; hg19: chr9-120475936;