X-12920352-C-T

Variant names:

• chrX-12920352-C-T
• rs5744081
• NM_138636.5:c.1312C>T

Variant summary

Our verdict is Likely benign. The variant received -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. 12/21 in silico tools predict 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
• Publications: 6 publications found

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:40720): (TLR8 antisense RNA 1)

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_138636.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR8	NM_138636.5	MANE Select	c.1312C>T	p.Arg438Trp	missense	Exon 2 of 2	NP_619542.1	Q9NR97-1
	TLR8	NM_016610.4		c.1366C>T	p.Arg456Trp	missense	Exon 3 of 3	NP_057694.2
	TLR8-AS1	NR_030727.1		n.241-12019G>A		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR8	ENST00000218032.7	TSL:1 MANE Select	c.1312C>T	p.Arg438Trp	missense	Exon 2 of 2	ENSP00000218032.7	Q9NR97-1
	TLR8	ENST00000311912.5	TSL:1	c.1366C>T	p.Arg456Trp	missense	Exon 3 of 3	ENSP00000312082.5	Q9NR97-2

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

African (AFR) AF: 0.00 AC: 0 AN: 26343

American (AMR) AF: 0.00 AC: 0 AN: 35077

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19365

East Asian (EAS) AF: 0.00 AC: 0 AN: 30181

South Asian (SAS) AF: 0.00 AC: 0 AN: 53877

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.00000713 AC: 6 AN: 841547

Other (OTH) AF: 0.00 AC: 0 AN: 46047

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		-0.66
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.066
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.015	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
Mutation Taster		=91/9	polymorphism

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: rs5744081; hg19: chrX-12938471;