9-117707870-A-G

Variant names:

• chr9-117707870-A-G
• rs1927910
• NM_138554.5:c.94-693A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138554.5(TLR4):​c.94-693A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.958 in 152,398 control chromosomes in the GnomAD database, including 70,238 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 0.96 (70190 hom., cov: 32)
  • Exomes 𝑓: 1.0 (48 hom.)
• Consequence: TLR4 NM_138554.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.322
• Publications: 6 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:):

RNU6-1082P (HGNC:48045): (RNA, U6 small nuclear 1082, pseudogene)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138554.5. 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.94-693A>G		intron	N/A	NP_612564.1
	TLR4	NM_003266.4		c.-147-329A>G		intron	N/A	NP_003257.1
	TLR4	NM_138557.3		c.-341+3305A>G		intron	N/A	NP_612567.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR4	ENST00000355622.8	TSL:1 MANE Select	c.94-693A>G		intron	N/A	ENSP00000363089.5
	TLR4	ENST00000394487.5	TSL:1	c.-147-329A>G		intron	N/A	ENSP00000377997.4
	ENSG00000285082	ENST00000697666.1		c.-147-329A>G		intron	N/A	ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.958 AC: 145790 AN: 152184 Hom.: 70149 Cov.: 32

Gnomad AFR AF: 0.854

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.985

Gnomad ASJ AF: 0.999

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.999

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.972

GnomAD4 exome AF: 1.00 AC: 96 AN: 96 Hom.: 48 AF XY: 1.00 AC XY: 56 AN XY: 56

African (AFR) AC: 0 AN: 0

American (AMR) AF: 1.00 AC: 8 AN: 8

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 1.00 AC: 2 AN: 2

South Asian (SAS) AF: 1.00 AC: 2 AN: 2

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 84 AN: 84

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.958 AC: 145888 AN: 152302 Hom.: 70190 Cov.: 32 AF XY: 0.960 AC XY: 71472 AN XY: 74464

African (AFR) AF: 0.854 AC: 35475 AN: 41546

American (AMR) AF: 0.985 AC: 15070 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.999 AC: 3467 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5180

South Asian (SAS) AF: 0.999 AC: 4824 AN: 4828

European-Finnish (FIN) AF: 1.00 AC: 10620 AN: 10620

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.999 AC: 67990 AN: 68038

Other (OTH) AF: 0.973 AC: 2058 AN: 2116

Alfa AF: 0.991 Hom.: 18693

Bravo AF: 0.952

Asia WGS AF: 0.989 AC: 3439 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.4
DANN	Benign	0.75
PhyloP100		-0.32
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: rs1927910; hg19: chr9-120470148;