9-117708220-A-C

Position:

• chr9-117708220-A-C

Variant summary

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

The ENST00000394487.5(TLR4):​c.-126A>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0347 in 1,090,370 control chromosomes in the GnomAD database, including 755 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 0.025 (82 hom., cov: 32)
  • Exomes 𝑓: 0.036 (673 hom.)
• Consequence: TLR4 ENST00000394487.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.540

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 (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0252 (3840/152300) while in subpopulation NFE AF= 0.0378 (2568/68016). AF 95% confidence interval is 0.0365. There are 82 homozygotes in gnomad4. There are 1704 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 82 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR4	NM_138554.5	c.94-343A>C		intron_variant		ENST00000355622.8
TLR4	NM_003266.4	c.-126A>C		5_prime_UTR_variant	2/4
TLR4	NM_138557.3	c.-341+3655A>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR4	ENST00000394487.5	c.-126A>C		5_prime_UTR_variant	2/4	1
TLR4	ENST00000355622.8	c.94-343A>C		intron_variant		1	NM_138554.5	P1
TLR4	ENST00000472304.2	c.93+3655A>C		intron_variant		1
TLR4	ENST00000490685.1	n.24A>C		non_coding_transcript_exon_variant	1/2	3

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3845 AN: 152182 Hom.: 82 Cov.: 32

Gnomad AFR AF: 0.00671

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0867

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.0106

Gnomad MID AF: 0.0633

Gnomad NFE AF: 0.0378

Gnomad OTH AF: 0.0339

GnomAD4 exome AF: 0.0363 AC: 34042 AN: 938070 Hom.: 673 Cov.: 30 AF XY: 0.0359 AC XY: 15808 AN XY: 439860

Gnomad4 AFR exome AF: 0.00618

Gnomad4 AMR exome AF: 0.0302

Gnomad4 ASJ exome AF: 0.0892

Gnomad4 EAS exome AF: 0.000299

Gnomad4 SAS exome AF: 0.0113

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0380

Gnomad4 OTH exome AF: 0.0361

GnomAD4 genome AF: 0.0252 AC: 3840 AN: 152300 Hom.: 82 Cov.: 32 AF XY: 0.0229 AC XY: 1704 AN XY: 74472

Gnomad4 AFR AF: 0.00669

Gnomad4 AMR AF: 0.0286

Gnomad4 ASJ AF: 0.0867

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0108

Gnomad4 FIN AF: 0.0106

Gnomad4 NFE AF: 0.0378

Gnomad4 OTH AF: 0.0331

Alfa AF: 0.0290 Hom.: 17

Bravo AF: 0.0268

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	5.5
DANN	Benign	0.46

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: rs11536871; hg19: chr9-120470498;