rs5030710

Variant names:

• chr9-117712443-T-C
• rs5030710
• NM_138554.5:c.315T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_138554.5(TLR4):​c.315T>C​(p.Ser105Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 1,613,892 control chromosomes in the GnomAD database, including 933 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.044 (492 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (441 hom.)
• Consequence: TLR4 NM_138554.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• Publications: 22 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]

ENSG00000285082 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP7: Synonymous conserved (PhyloP=-0.224 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.315T>C	p.Ser105Ser	synonymous_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.195T>C	p.Ser65Ser	synonymous_variant	Exon 4 of 4		NP_003257.1
TLR4	NM_138557.3	c.-286T>C		5_prime_UTR_variant	Exon 2 of 2		NP_612567.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR4	ENST00000355622.8	c.315T>C	p.Ser105Ser	synonymous_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.140+3714T>C		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6655 AN: 152140 Hom.: 492 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000764

Gnomad OTH AF: 0.0277

GnomAD2 exomes AF: 0.0116 AC: 2899 AN: 250678 AF XY: 0.00863

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.00844

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000698

Gnomad OTH exome AF: 0.00656

GnomAD4 exome AF: 0.00471 AC: 6884 AN: 1461634 Hom.: 441 Cov.: 31 AF XY: 0.00405 AC XY: 2947 AN XY: 727124

African (AFR) AF: 0.155 AC: 5191 AN: 33460

American (AMR) AF: 0.00964 AC: 431 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00214 AC: 56 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.000290 AC: 25 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00798 AC: 46 AN: 5764

European-Non Finnish (NFE) AF: 0.000451 AC: 502 AN: 1111880

Other (OTH) AF: 0.0105 AC: 633 AN: 60384

GnomAD4 genome AF: 0.0438 AC: 6666 AN: 152258 Hom.: 492 Cov.: 32 AF XY: 0.0427 AC XY: 3180 AN XY: 74444

African (AFR) AF: 0.151 AC: 6276 AN: 41516

American (AMR) AF: 0.0167 AC: 256 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000764 AC: 52 AN: 68022

Other (OTH) AF: 0.0274 AC: 58 AN: 2114

Alfa AF: 0.0175 Hom.: 142

Bravo AF: 0.0492

Asia WGS AF: 0.0110 AC: 37 AN: 3478

EpiCase AF: 0.000764

EpiControl AF: 0.000830

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	2.8
DANN	Benign	0.72
PhyloP100		-0.22
Mutation Taster		=100/0	polymorphism (auto)

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: rs5030710; hg19: chr9-120474721;