rs5744077

chrX-12919068-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138636.5(TLR8):c.28A>G(p.Met10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00674 in 1,206,978 control chromosomes in the GnomAD database, including 320 homozygotes. There are 2,184 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.033 (178 hom., 979 hem., cov: 23)
  • Exomes 𝑓: 0.0040 (142 hom. 1205 hem.)
• Consequence: TLR8 NM_138636.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.507

Genes affected

TLR8 (HGNC:15632): (toll like receptor 8) 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 (PAMPs) 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. This gene is predominantly expressed in lung and peripheral blood leukocytes, and lies in close proximity to another family member, TLR7, on chromosome X. [provided by RefSeq, Jul 2008]

TLR8-AS1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017362535).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR8	NM_138636.5	c.28A>G	p.Met10Val	missense_variant	2/2	ENST00000218032.7
TLR8-AS1	NR_030727.1	n.241-10735T>C		intron_variant, non_coding_transcript_variant
TLR8	NM_016610.4	c.82A>G	p.Met28Val	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR8	ENST00000218032.7	c.28A>G	p.Met10Val	missense_variant	2/2	1	NM_138636.5	P2
TLR8	ENST00000311912.5	c.82A>G	p.Met28Val	missense_variant	3/3	1		A2

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 3750 AN: 112078 Hom.: 178 Cov.: 23 AF XY: 0.0285 AC XY: 975 AN XY: 34256

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00852

Gnomad ASJ AF: 0.00415

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0209

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.0224

GnomAD3 exomes AF: 0.0103 AC: 1835 AN: 178640 Hom.: 79 AF XY: 0.00712 AC XY: 452 AN XY: 63444

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00224

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000225

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000825

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00401 AC: 4390 AN: 1094847 Hom.: 142 Cov.: 30 AF XY: 0.00334 AC XY: 1205 AN XY: 360649

Gnomad4 AFR exome AF: 0.118

Gnomad4 AMR exome AF: 0.00524

Gnomad4 ASJ exome AF: 0.00234

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000410

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000665

Gnomad4 OTH exome AF: 0.00940

GnomAD4 genome AF: 0.0334 AC: 3750 AN: 112131 Hom.: 178 Cov.: 23 AF XY: 0.0285 AC XY: 979 AN XY: 34319

Gnomad4 AFR AF: 0.116

Gnomad4 AMR AF: 0.00841

Gnomad4 ASJ AF: 0.00415

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000364

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000882

Gnomad4 OTH AF: 0.0221

Alfa AF: 0.00466 Hom.: 252

Bravo AF: 0.0387

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.115 AC: 442

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.0112 AC: 1361

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.92	T
BayesDel_noAF	Benign	-0.99
Cadd	Benign	0.036
Dann	Benign	0.41
DEOGEN2	Benign	0.096	T;.
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.39	T;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.20	N;N
REVEL	Benign	0.045
Sift	Benign	0.15	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0	B;.
Vest4		0.040
MPC		0.76
ClinPred		0.0012	T
GERP RS		0.30
Varity_R		0.064
gMVP		0.36

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5744077; hg19: chrX-12937187;