rs5030721

Positions:

• chr9-117714087-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_138554.5(TLR4):​c.1959G>A​(p.Lys653=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,614,034 control chromosomes in the GnomAD database, including 117 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0083 (7 hom., cov: 32)
  • Exomes 𝑓: 0.011 (110 hom.)
• Consequence: TLR4 NM_138554.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.391

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 9-117714087-G-A is Benign according to our data. Variant chr9-117714087-G-A is described in ClinVar as [Benign]. Clinvar id is 786820.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.391 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 7 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR4	NM_138554.5	c.1959G>A	p.Lys653=	synonymous_variant	3/3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.1839G>A	p.Lys613=	synonymous_variant	4/4		NP_003257.1
TLR4	NM_138557.3	c.1359G>A	p.Lys453=	synonymous_variant	2/2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8	c.1959G>A	p.Lys653=	synonymous_variant	3/3	1	NM_138554.5	ENSP00000363089	P1
TLR4	ENST00000394487.5	c.1839G>A	p.Lys613=	synonymous_variant	4/4	1		ENSP00000377997
TLR4	ENST00000472304.2	c.*1693G>A		3_prime_UTR_variant	2/2	1		ENSP00000496429

Frequencies

GnomAD3 genomes AF: 0.00829 AC: 1261 AN: 152140 Hom.: 7 Cov.: 32

Gnomad AFR AF: 0.00183

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00687

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0118

Gnomad FIN AF: 0.0187

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0118

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00896 AC: 2248 AN: 250906 Hom.: 19 AF XY: 0.00960 AC XY: 1302 AN XY: 135598

Gnomad AFR exome AF: 0.00154

Gnomad AMR exome AF: 0.00640

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0138

Gnomad FIN exome AF: 0.0148

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00867

GnomAD4 exome AF: 0.0112 AC: 16403 AN: 1461776 Hom.: 110 Cov.: 32 AF XY: 0.0112 AC XY: 8174 AN XY: 727188

Gnomad4 AFR exome AF: 0.00117

Gnomad4 AMR exome AF: 0.00626

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0131

Gnomad4 FIN exome AF: 0.0142

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.00967

GnomAD4 genome AF: 0.00828 AC: 1261 AN: 152258 Hom.: 7 Cov.: 32 AF XY: 0.00873 AC XY: 650 AN XY: 74446

Gnomad4 AFR AF: 0.00183

Gnomad4 AMR AF: 0.00686

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0118

Gnomad4 FIN AF: 0.0187

Gnomad4 NFE AF: 0.0118

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00899 Hom.: 6

Bravo AF: 0.00624

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0105

EpiControl AF: 0.0103

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	TLR4: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 21, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	3.6
DANN	Benign	0.63

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: rs5030721; hg19: chr9-120476365;