rs5030718

chr9-117713548-G-Achr9-117713548-G-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_138554.5(TLR4):c.1420G>A(p.Glu474Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00212 in 1,613,926 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.011 (31 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (22 hom.)
• Consequence: TLR4 NM_138554.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.547

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030899942).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0111 (1686/152146) while in subpopulation AFR AF= 0.0385 (1598/41498). AF 95% confidence interval is 0.0369. There are 31 homozygotes in gnomad4. There are 787 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 31 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.1420G>A	p.Glu474Lys	missense_variant	3/3	ENST00000355622.8
TLR4	NM_003266.4	c.1300G>A	p.Glu434Lys	missense_variant	4/4
TLR4	NM_138557.3	c.820G>A	p.Glu274Lys	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000355622.8	c.1420G>A	p.Glu474Lys	missense_variant	3/3	1	NM_138554.5	P1
TLR4	ENST00000394487.5	c.1300G>A	p.Glu434Lys	missense_variant	4/4	1
TLR4	ENST00000472304.2	c.*1154G>A		3_prime_UTR_variant	2/2	1

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1685 AN: 152028 Hom.: 31 Cov.: 32

Gnomad AFR AF: 0.0386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00309

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00813

GnomAD3 exomes AF: 0.00308 AC: 773 AN: 250658 Hom.: 9 AF XY: 0.00224 AC XY: 304 AN XY: 135458

Gnomad AFR exome AF: 0.0397

Gnomad AMR exome AF: 0.00153

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00277

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000150

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.00118 AC: 1729 AN: 1461780 Hom.: 22 Cov.: 32 AF XY: 0.00106 AC XY: 774 AN XY: 727186

Gnomad4 AFR exome AF: 0.0380

Gnomad4 AMR exome AF: 0.00183

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00262

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000899

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.0111 AC: 1686 AN: 152146 Hom.: 31 Cov.: 32 AF XY: 0.0106 AC XY: 787 AN XY: 74382

Gnomad4 AFR AF: 0.0385

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00309

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00805

Alfa AF: 0.00237 Hom.: 7

Bravo AF: 0.0126

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0402 AC: 177

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00380 AC: 461

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000273

EpiControl AF: 0.000296

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.70
Cadd	Benign	0.13
Dann	Benign	0.29
Eigen	Benign	-2.2
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.78	T;.;T
MetaRNN	Benign	0.0031	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.26	N;.;N
REVEL	Benign	0.042
Sift	Benign	0.37	T;.;T
Sift4G	Benign	0.67	T;.;T
Polyphen		0.0010	.;B;B
Vest4		0.046
MVP		0.45
MPC		0.096
ClinPred		0.0090	T
GERP RS		-10
Varity_R		0.15
gMVP		0.20

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: rs5030718; hg19: chr9-120475826;