X-12919068-A-G

Variant names:

• chrX-12919068-A-G
• rs5744077
• NM_138636.5:c.28A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_138636.5(TLR8):​c.28A>G​(p.Met10Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00674 in 1,206,978 control chromosomes in the GnomAD database, including 320 homozygotes. There are 2,184 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.033 (178 hom., 979 hem., cov: 23)
  • Exomes 𝑓: 0.0040 (142 hom. 1205 hem.)
• Consequence: TLR8 NM_138636.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.507
• Publications: 13 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017362535).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR8	NM_138636.5	MANE Select	c.28A>G	p.Met10Val	missense	Exon 2 of 2	NP_619542.1
	TLR8	NM_016610.4		c.82A>G	p.Met28Val	missense	Exon 3 of 3	NP_057694.2
	TLR8-AS1	NR_030727.1		n.241-10735T>C		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR8	ENST00000218032.7	TSL:1 MANE Select	c.28A>G	p.Met10Val	missense	Exon 2 of 2	ENSP00000218032.7
	TLR8	ENST00000311912.5	TSL:1	c.82A>G	p.Met28Val	missense	Exon 3 of 3	ENSP00000312082.5

Frequencies

GnomAD3 genomes AF: 0.0335 AC: 3750 AN: 112078 Hom.: 178 Cov.: 23

Gnomad AFR AF: 0.116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00852

Gnomad ASJ AF: 0.00415

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0209

Gnomad NFE AF: 0.000882

Gnomad OTH AF: 0.0224

GnomAD2 exomes AF: 0.0103 AC: 1835 AN: 178640 AF XY: 0.00712

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.00497

Gnomad ASJ exome AF: 0.00224

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000825

Gnomad OTH exome AF: 0.00408

GnomAD4 exome AF: 0.00401 AC: 4390 AN: 1094847 Hom.: 142 Cov.: 30 AF XY: 0.00334 AC XY: 1205 AN XY: 360649

African (AFR) AF: 0.118 AC: 3093 AN: 26319

American (AMR) AF: 0.00524 AC: 183 AN: 34904

Ashkenazi Jewish (ASJ) AF: 0.00234 AC: 45 AN: 19226

East Asian (EAS) AF: 0.00 AC: 0 AN: 30163

South Asian (SAS) AF: 0.000410 AC: 22 AN: 53643

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40462

Middle Eastern (MID) AF: 0.0136 AC: 56 AN: 4118

European-Non Finnish (NFE) AF: 0.000665 AC: 559 AN: 840048

Other (OTH) AF: 0.00940 AC: 432 AN: 45964

GnomAD4 genome AF: 0.0334 AC: 3750 AN: 112131 Hom.: 178 Cov.: 23 AF XY: 0.0285 AC XY: 979 AN XY: 34319

African (AFR) AF: 0.116 AC: 3563 AN: 30729

American (AMR) AF: 0.00841 AC: 89 AN: 10580

Ashkenazi Jewish (ASJ) AF: 0.00415 AC: 11 AN: 2648

East Asian (EAS) AF: 0.00 AC: 0 AN: 3609

South Asian (SAS) AF: 0.000364 AC: 1 AN: 2750

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6101

Middle Eastern (MID) AF: 0.0229 AC: 5 AN: 218

European-Non Finnish (NFE) AF: 0.000882 AC: 47 AN: 53273

Other (OTH) AF: 0.0221 AC: 34 AN: 1538

Alfa AF: 0.0130 Hom.: 953

Bravo AF: 0.0387

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.115 AC: 442

ESP6500EA AF: 0.000892 AC: 6

ExAC AF: 0.0112 AC: 1361

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.92	T
BayesDel_noAF	Benign	-0.99
CADD	Benign	0.036
DANN	Benign	0.41
DEOGEN2	Benign	0.096	T
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.39	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.51
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.045
Sift	Benign	0.15	T
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.040
MPC		0.76
ClinPred		0.0012	T
GERP RS		0.30
Varity_R		0.064
gMVP		0.36
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs5744077; hg19: chrX-12937187;