X-12921293-C-G

Variant names:

• chrX-12921293-C-G
• rs3747414
• NM_138636.5:c.2253C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_138636.5(TLR8):​c.2253C>G​(p.Ile751Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. Synonymous variant affecting the same amino acid position (i.e. I751I) has been classified as Benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: TLR8 NM_138636.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.177
• Publications: 32 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR8	NM_138636.5	c.2253C>G	p.Ile751Met	missense_variant	Exon 2 of 2	ENST00000218032.7	NP_619542.1
TLR8	NM_016610.4	c.2307C>G	p.Ile769Met	missense_variant	Exon 3 of 3		NP_057694.2
TLR8-AS1	NR_030727.1	n.241-12960G>C		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR8	ENST00000218032.7	c.2253C>G	p.Ile751Met	missense_variant	Exon 2 of 2	1	NM_138636.5	ENSP00000218032.7
TLR8	ENST00000311912.5	c.2307C>G	p.Ile769Met	missense_variant	Exon 3 of 3	1		ENSP00000312082.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;.
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.85	T;T
M_CAP	Pathogenic	0.54	D
MetaRNN	Uncertain	0.68	D;D
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Uncertain	2.8	M;.
PhyloP100		-0.18
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N;N
REVEL	Benign	0.23
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.99	D;.
Vest4		0.21
MutPred		0.36		Gain of ubiquitination at K749 (P = 0.0412);.;
MVP		0.62
MPC		1.7
ClinPred		0.91	D
GERP RS		4.0
Varity_R		0.76
gMVP		0.82
Mutation Taster		=54/46	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: rs3747414; hg19: chrX-12939412;