chr9-117704214-G-C

Variant names:

• chr9-117704214-G-C
• rs41391946
• ENST00000394487.5:c.-499G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000394487.5(TLR4):​c.-499G>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 0.000874 in 473,722 control chromosomes in the GnomAD database, including 6 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 0.00081 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00091 (6 hom.)
• Consequence: TLR4 ENST00000394487.5 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.16
• Publications: 4 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000808 (123/152272) while in subpopulation EAS AF = 0.0214 (111/5182). AF 95% confidence interval is 0.0182. There are 0 homozygotes in GnomAd4. There are 82 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000394487.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	NM_138554.5	MANE Select	c.-259G>C		upstream_gene	N/A	NP_612564.1
	TLR4	NM_003266.4		c.-499G>C		upstream_gene	N/A	NP_003257.1
	TLR4	NM_138557.3		c.-692G>C		upstream_gene	N/A	NP_612567.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000394487.5	TSL:1	c.-499G>C		5_prime_UTR	Exon 1 of 4	ENSP00000377997.4
	TLR4	ENST00000472304.2	TSL:1	c.-259G>C		5_prime_UTR	Exon 1 of 2	ENSP00000496429.1
	ENSG00000285082	ENST00000642985.1		n.-259G>C		non_coding_transcript_exon	Exon 1 of 5	ENSP00000493686.1

Frequencies

GnomAD3 genomes AF: 0.000815 AC: 124 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0216

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 0.000905 AC: 291 AN: 321450 Hom.: 6 Cov.: 0 AF XY: 0.000971 AC XY: 165 AN XY: 169994

African (AFR) AF: 0.000104 AC: 1 AN: 9624

American (AMR) AF: 0.00 AC: 0 AN: 13650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9732

East Asian (EAS) AF: 0.0105 AC: 216 AN: 20640

South Asian (SAS) AF: 0.00176 AC: 68 AN: 38708

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 18110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1372

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 191238

Other (OTH) AF: 0.000327 AC: 6 AN: 18376

GnomAD4 genome AF: 0.000808 AC: 123 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00110 AC XY: 82 AN XY: 74458

African (AFR) AF: 0.0000481 AC: 2 AN: 41552

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0214 AC: 111 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000835

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.11
DANN	Benign	0.53
PhyloP100		-1.2
PromoterAI		0.085	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs41391946; hg19: chr9-120466492;