rs3764880

chrX-12906707-A-GchrX-12906707-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 8P and 10B. PVS1 BP6_Moderate BA1

The NM_138636.5(TLR8):c.1A>G(p.Met1?) variant causes a start lost, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,107,953 control chromosomes in the GnomAD database, including 35,042 homozygotes. There are 98,465 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.30 (4102 hom., 10375 hem., cov: 24)
  • Exomes 𝑓: 0.28 (30940 hom. 88090 hem.)
• Consequence: TLR8 NM_138636.5 start_lost, splice_region
• Scores: Splicing: ADA: 0.00004202
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.617

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• BP6: Variant X-12906707-A-G is Benign according to our data. Variant chrX-12906707-A-G is described in ClinVar as [Benign]. Clinvar id is 2688133.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.782 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR8	NM_138636.5	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/2	ENST00000218032.7
TLR8-AS1	NR_030727.1	n.359-456T>C		intron_variant, non_coding_transcript_variant
TLR8	NM_016610.4	c.-83A>G		splice_region_variant, 5_prime_UTR_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR8	ENST00000218032.7	c.1A>G	p.Met1?	start_lost, splice_region_variant	1/2	1	NM_138636.5	P2
TLR8	ENST00000311912.5	c.-83A>G		splice_region_variant, 5_prime_UTR_variant	1/3	1		A2
TLR8-AS1	ENST00000451564.1	n.119-456T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.304 AC: 33957 AN: 111550 Hom.: 4105 Cov.: 24 AF XY: 0.307 AC XY: 10345 AN XY: 33750

Gnomad AFR AF: 0.270

Gnomad AMI AF: 0.381

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.807

Gnomad SAS AF: 0.532

Gnomad FIN AF: 0.199

Gnomad MID AF: 0.349

Gnomad NFE AF: 0.254

Gnomad OTH AF: 0.341

GnomAD3 exomes AF: 0.310 AC: 36412 AN: 117570 Hom.: 5255 AF XY: 0.300 AC XY: 10830 AN XY: 36126

Gnomad AFR exome AF: 0.251

Gnomad AMR exome AF: 0.495

Gnomad ASJ exome AF: 0.322

Gnomad EAS exome AF: 0.799

Gnomad SAS exome AF: 0.457

Gnomad FIN exome AF: 0.199

Gnomad NFE exome AF: 0.232

Gnomad OTH exome AF: 0.278

GnomAD4 exome AF: 0.281 AC: 279874 AN: 996348 Hom.: 30940 Cov.: 28 AF XY: 0.280 AC XY: 88090 AN XY: 314368

Gnomad4 AFR exome AF: 0.256

Gnomad4 AMR exome AF: 0.475

Gnomad4 ASJ exome AF: 0.369

Gnomad4 EAS exome AF: 0.791

Gnomad4 SAS exome AF: 0.451

Gnomad4 FIN exome AF: 0.210

Gnomad4 NFE exome AF: 0.252

Gnomad4 OTH exome AF: 0.324

GnomAD4 genome AF: 0.305 AC: 33985 AN: 111605 Hom.: 4102 Cov.: 24 AF XY: 0.307 AC XY: 10375 AN XY: 33815

Gnomad4 AFR AF: 0.271

Gnomad4 AMR AF: 0.455

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.807

Gnomad4 SAS AF: 0.530

Gnomad4 FIN AF: 0.199

Gnomad4 NFE AF: 0.254

Gnomad4 OTH AF: 0.344

Alfa AF: 0.294 Hom.: 30122

Bravo AF: 0.329

TwinsUK AF: 0.263 AC: 975

ALSPAC AF: 0.244 AC: 705

ESP6500AA AF: 0.264 AC: 1013

ESP6500EA AF: 0.247 AC: 1664

ExAC AF: 0.359 AC: 43348

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 48% of patients studied by a panel of primary immunodeficiencies. Number of patients: 46. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-1.0	T
BayesDel_noAF	Benign	-1.1
Cadd	Benign	0.027
Dann	Benign	0.24
DEOGEN2	Benign	0.098	T
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0000015	T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	P;P
PROVEAN	Benign	0.060	N
REVEL	Benign	0.11
Sift	Pathogenic	0.0	D
Sift4G	Benign	0.37	T
Polyphen		0.0	B
Vest4		0.010
ClinPred		0.0039	T
GERP RS		-3.6
Varity_R		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.022
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

Publications

LitVar

Other links and lift over

dbSNP: rs3764880; hg19: chrX-12924826; COSMIC: COSV54317142;