Genetic Variant TLR8-AS1:n.119-327G>A (chrX-12906578-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NR_030727.1(TLR8-AS1):n.359-327G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000252 in 397,604 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: 24)

Exomes 𝑓: 0.0000025 ( 0 hom. 0 hem. )

Consequence

TLR8-AS1
NR_030727.1 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0960

Publications

74 publications found

Variant links:

Genes affected

TLR8-AS1 (HGNC:40720): (TLR8 antisense RNA 1)

TLR8-AS1 links:

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 Gene-Disease associations (from GenCC):

immunodeficiency 98 with autoinflammation, X-linked
Inheritance: Unknown, XL Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), PanelApp Australia

TLR8 links:

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ACMG classification

Classification was made for transcript

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 (BayesDel_noAF=-0.86).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NR_030727.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TLR8-AS1	NR_030727.1		n.359-327G>A	intron	N/A
TLR8	NM_138636.5	MANE Select	c.-129C>T	upstream_gene	N/A	NP_619542.1	Q9NR97-1
TLR8	NM_016610.4		c.-212C>T	upstream_gene	N/A	NP_057694.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TLR8-AS1	ENST00000451564.1	TSL:5	n.119-327G>A	intron	N/A
TLR8	ENST00000218032.7	TSL:1 MANE Select	c.-129C>T	upstream_gene	N/A	ENSP00000218032.7	Q9NR97-1
TLR8	ENST00000311912.5	TSL:1	c.-212C>T	upstream_gene	N/A	ENSP00000312082.5	Q9NR97-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000252

AC:

AN:

397604

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

101888

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

10062

American (AMR)

AF:

0.00

AC:

AN:

11916

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

8391

East Asian (EAS)

AF:

0.00

AC:

AN:

20871

South Asian (SAS)

AF:

0.00

AC:

AN:

8538

European-Finnish (FIN)

AF:

0.00

AC:

AN:

30684

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2432

European-Non Finnish (NFE)

AF:

0.00000351

AC:

AN:

285104

Other (OTH)

AF:

0.00

AC:

AN:

19606

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

4.7

(source)

DANN

Benign

0.96

PhyloP100

-0.096

PromoterAI

-0.091

Neutral

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over