X-12919339-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_138636.5(TLR8):c.299T>C(p.Val100Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000322 in 1,209,607 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.000033 (0 hom. 16 hem.)
• Consequence: TLR8 NM_138636.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.06

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.049483657).
• BS2: High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR8	NM_138636.5	c.299T>C	p.Val100Ala	missense_variant	2/2	ENST00000218032.7
TLR8-AS1	NR_030727.1	n.241-11006A>G		intron_variant, non_coding_transcript_variant
TLR8	NM_016610.4	c.353T>C	p.Val118Ala	missense_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR8	ENST00000218032.7	c.299T>C	p.Val100Ala	missense_variant	2/2	1	NM_138636.5	P2
TLR8	ENST00000311912.5	c.353T>C	p.Val118Ala	missense_variant	3/3	1		A2

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111655 Hom.: 0 Cov.: 23 AF XY: 0.0000887 AC XY: 3 AN XY: 33837

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000372

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.000669

GnomAD3 exomes AF: 0.0000383 AC: 7 AN: 182857 Hom.: 0 AF XY: 0.0000592 AC XY: 4 AN XY: 67587

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000210

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000368

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 36 AN: 1097952 Hom.: 0 Cov.: 31 AF XY: 0.0000440 AC XY: 16 AN XY: 363312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000462

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000131

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111655 Hom.: 0 Cov.: 23 AF XY: 0.0000887 AC XY: 3 AN XY: 33837

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000372

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.000669

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2024

The c.299T>C (p.V100A) alteration is located in exon 2 (coding exon 2) of the TLR8 gene. This alteration results from a T to C substitution at nucleotide position 299, causing the valine (V) at amino acid position 100 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.81	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.057
Dann	Benign	0.58
DEOGEN2	Benign	0.10	T;.
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.46	T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	0.090	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	0.80	N;N
REVEL	Benign	0.012
Sift	Benign	0.29	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.0	B;.
Vest4		0.016
MutPred		0.36		Gain of disorder (P = 0.0716);.;
MVP		0.14
MPC		0.90
ClinPred		0.059	T
GERP RS		-6.7
Varity_R		0.075
gMVP		0.45

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: rs200981848; hg19: chrX-12937458; COSMIC: COSV54321173;