X-12919685-C-A

Variant names:

• chrX-12919685-C-A
• NM_138636.5:c.645C>A
• TLR8 p.His215Gln

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_138636.5(TLR8):​c.645C>A​(p.His215Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. H215H) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: TLR8 NM_138636.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.52
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047213882).

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.645C>A	p.His215Gln	missense	Exon 2 of 2	NP_619542.1	Q9NR97-1
	TLR8	NM_016610.4		c.699C>A	p.His233Gln	missense	Exon 3 of 3	NP_057694.2
	TLR8-AS1	NR_030727.1		n.241-11352G>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR8	ENST00000218032.7	TSL:1 MANE Select	c.645C>A	p.His215Gln	missense	Exon 2 of 2	ENSP00000218032.7	Q9NR97-1
	TLR8	ENST00000311912.5	TSL:1	c.699C>A	p.His233Gln	missense	Exon 3 of 3	ENSP00000312082.5	Q9NR97-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.11e-7 AC: 1 AN: 1097374 Hom.: 0 Cov.: 34 AF XY: 0.00000276 AC XY: 1 AN XY: 362750

African (AFR) AF: 0.00 AC: 0 AN: 26395

American (AMR) AF: 0.00 AC: 0 AN: 35161

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19373

East Asian (EAS) AF: 0.00 AC: 0 AN: 30199

South Asian (SAS) AF: 0.00 AC: 0 AN: 54030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40510

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841503

Other (OTH) AF: 0.00 AC: 0 AN: 46071

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.0010
DANN	Benign	0.60
DEOGEN2	Benign	0.086	T
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0078	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.60	N
PhyloP100		-4.5
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.76	N
REVEL	Benign	0.015
Sift	Benign	0.30	T
Sift4G	Benign	0.37	T
Varity_R		0.22
gMVP		0.35
Mutation Taster		=95/5	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chrX-12937804;