NM_138554.5:c.*6014T>C

Variant names:

• chr9-117720662-T-C
• rs7846989
• NM_138554.5:c.*6014T>C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_138554.5(TLR4):​c.*6014T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.174 in 152,134 control chromosomes in the GnomAD database, including 3,463 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 0.17 (3463 hom., cov: 32)
  • Exomes 𝑓: 0.33 (0 hom.)
• Consequence: TLR4 NM_138554.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.284

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.365 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR4	NM_138554.5	c.*6014T>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000355622.8	NP_612564.1
TLR4	NM_003266.4	c.*6014T>C		3_prime_UTR_variant	Exon 4 of 4		NP_003257.1
TLR4	NM_138557.3	c.*6014T>C		3_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.*6014T>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_138554.5	ENSP00000363089.5
ENSG00000285082	ENST00000697666.1	c.140+11933T>C		intron_variant	Intron 3 of 4			ENSP00000513391.1

Frequencies

GnomAD3 genomes AF: 0.174 AC: 26478 AN: 152004 Hom.: 3455 Cov.: 32

Gnomad AFR AF: 0.370

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0965

Gnomad ASJ AF: 0.0806

Gnomad EAS AF: 0.0435

Gnomad SAS AF: 0.181

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0951

Gnomad OTH AF: 0.146

GnomAD4 exome AF: 0.333 AC: 4 AN: 12 Hom.: 0 Cov.: 0 AF XY: 0.250 AC XY: 2 AN XY: 8

Gnomad4 AFR exome AF: 0.500

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.375

GnomAD4 genome AF: 0.174 AC: 26524 AN: 152122 Hom.: 3463 Cov.: 32 AF XY: 0.176 AC XY: 13060 AN XY: 74384

Gnomad4 AFR AF: 0.370

Gnomad4 AMR AF: 0.0963

Gnomad4 ASJ AF: 0.0806

Gnomad4 EAS AF: 0.0438

Gnomad4 SAS AF: 0.181

Gnomad4 FIN AF: 0.141

Gnomad4 NFE AF: 0.0951

Gnomad4 OTH AF: 0.146

Alfa AF: 0.102 Hom.: 1019

Bravo AF: 0.176

Asia WGS AF: 0.143 AC: 495 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	8.1
DANN	Benign	0.79

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs7846989; hg19: chr9-120482940;