X-12919685-C-T

Variant names:

• chrX-12919685-C-T
• rs5744080
• NM_138636.5:c.645C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_138636.5(TLR8):​c.645C>T​(p.His215His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,097,286 control chromosomes in the GnomAD database, including 74,596 homozygotes. There are 160,196 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.54 (12589 hom., 17416 hem., cov: 22)
  • Exomes 𝑓: 0.44 (74596 hom. 160196 hem.)
  • Failed GnomAD Quality Control
• Consequence: TLR8 NM_138636.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -4.52
• Publications: 39 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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant X-12919685-C-T is Benign according to our data. Variant chrX-12919685-C-T is described in ClinVar as Benign. ClinVar VariationId is 2688009.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-4.52 with no splicing effect.
• BA1: GnomAdExome4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.799 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR8	NM_138636.5	c.645C>T	p.His215His	synonymous_variant	Exon 2 of 2	ENST00000218032.7	NP_619542.1
TLR8	NM_016610.4	c.699C>T	p.His233His	synonymous_variant	Exon 3 of 3		NP_057694.2
TLR8-AS1	NR_030727.1	n.241-11352G>A		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR8	ENST00000218032.7	c.645C>T	p.His215His	synonymous_variant	Exon 2 of 2	1	NM_138636.5	ENSP00000218032.7
TLR8	ENST00000311912.5	c.699C>T	p.His233His	synonymous_variant	Exon 3 of 3	1		ENSP00000312082.5

Frequencies

GnomAD3 genomes AF: 0.539 AC: 59381 AN: 110085 Hom.: 12582 Cov.: 22

Gnomad AFR AF: 0.766

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.625

Gnomad ASJ AF: 0.477

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.623

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.460

Gnomad NFE AF: 0.390

Gnomad OTH AF: 0.543

GnomAD2 exomes AF: 0.524 AC: 95416 AN: 182112 AF XY: 0.510

Gnomad AFR exome AF: 0.769

Gnomad AMR exome AF: 0.679

Gnomad ASJ exome AF: 0.465

Gnomad EAS exome AF: 0.800

Gnomad FIN exome AF: 0.421

Gnomad NFE exome AF: 0.389

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.438 AC: 480707 AN: 1097286 Hom.: 74596 Cov.: 34 AF XY: 0.442 AC XY: 160196 AN XY: 362736

African (AFR) AF: 0.777 AC: 20516 AN: 26391

American (AMR) AF: 0.678 AC: 23823 AN: 35152

Ashkenazi Jewish (ASJ) AF: 0.465 AC: 9002 AN: 19373

East Asian (EAS) AF: 0.807 AC: 24370 AN: 30197

South Asian (SAS) AF: 0.616 AC: 33291 AN: 54028

European-Finnish (FIN) AF: 0.428 AC: 17355 AN: 40508

Middle Eastern (MID) AF: 0.486 AC: 2008 AN: 4132

European-Non Finnish (NFE) AF: 0.390 AC: 328328 AN: 841439

Other (OTH) AF: 0.478 AC: 22014 AN: 46066

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.540 AC: 59447 AN: 110139 Hom.: 12589 Cov.: 22 AF XY: 0.538 AC XY: 17416 AN XY: 32393

African (AFR) AF: 0.766 AC: 23172 AN: 30232

American (AMR) AF: 0.626 AC: 6419 AN: 10256

Ashkenazi Jewish (ASJ) AF: 0.477 AC: 1255 AN: 2630

East Asian (EAS) AF: 0.799 AC: 2821 AN: 3530

South Asian (SAS) AF: 0.622 AC: 1626 AN: 2615

European-Finnish (FIN) AF: 0.401 AC: 2310 AN: 5757

Middle Eastern (MID) AF: 0.474 AC: 102 AN: 215

European-Non Finnish (NFE) AF: 0.390 AC: 20588 AN: 52723

Other (OTH) AF: 0.546 AC: 826 AN: 1512

Alfa AF: 0.443 Hom.: 28896

Bravo AF: 0.571

EpiCase AF: 0.385

EpiControl AF: 0.399

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jan 24, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 73% of patients studied by a panel of primary immunodeficiencies. Number of patients: 69. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.0080
DANN	Benign	0.69
PhyloP100		-4.5
Mutation Taster		=61/39	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: rs5744080; hg19: chrX-12937804; COSMIC: COSV54316943;