chrX-12920352-C-T

Position:

• chrX-12920352-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_138636.5(TLR8):​c.1312C>T​(p.Arg438Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000547 in 1,096,984 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. 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: not found (cov: 23)
  • Exomes 𝑓: 0.0000055 (0 hom. 2 hem.)
• Consequence: TLR8 NM_138636.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.659

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21082863).
• BS2: High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR8	NM_138636.5	c.1312C>T	p.Arg438Trp	missense_variant	2/2	ENST00000218032.7	NP_619542.1
TLR8	NM_016610.4	c.1366C>T	p.Arg456Trp	missense_variant	3/3		NP_057694.2
TLR8-AS1	NR_030727.1	n.241-12019G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR8	ENST00000218032.7	c.1312C>T	p.Arg438Trp	missense_variant	2/2	1	NM_138636.5	ENSP00000218032.7
TLR8	ENST00000311912.5	c.1366C>T	p.Arg456Trp	missense_variant	3/3	1		ENSP00000312082.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000547 AC: 6 AN: 1096984 Hom.: 0 Cov.: 34 AF XY: 0.00000552 AC XY: 2 AN XY: 362438

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000713

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
FATHMM_MKL	Benign	0.048	N
LIST_S2	Uncertain	0.91	D;D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M;.
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.066
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;.
Vest4		0.22
MutPred		0.47		Loss of disorder (P = 0.0049);.;
MVP		0.18
MPC		1.4
ClinPred		0.91	D
GERP RS		-0.83
Varity_R		0.071
gMVP		0.28

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: rs5744081; hg19: chrX-12938471;