rs3764880

Variant names:

• chrX-12906707-A-G
• rs3764880
• NM_138636.5:c.1A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-12906707-A-G
• chrX-12906707-A-T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. 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
• Publications: 157 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 -10 ACMG points.

• BP6: Variant X-12906707-A-G is Benign according to our data. Variant chrX-12906707-A-G is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
TLR8	NM_138636.5	c.1A>G	p.Met1?	start_lost, splice_region_variant	Exon 1 of 2	ENST00000218032.7	NP_619542.1
TLR8	NM_016610.4	c.-83A>G		splice_region_variant	Exon 1 of 3		NP_057694.2
TLR8	NM_016610.4	c.-83A>G		5_prime_UTR_variant	Exon 1 of 3		NP_057694.2
TLR8-AS1	NR_030727.1	n.359-456T>C		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR8	ENST00000218032.7	c.1A>G	p.Met1?	start_lost, splice_region_variant	Exon 1 of 2	1	NM_138636.5	ENSP00000218032.7
TLR8	ENST00000311912.5	c.-83A>G		splice_region_variant	Exon 1 of 3	1		ENSP00000312082.5
TLR8	ENST00000311912.5	c.-83A>G		5_prime_UTR_variant	Exon 1 of 3	1		ENSP00000312082.5
TLR8-AS1	ENST00000451564.1	n.119-456T>C		intron_variant	Intron 1 of 2	5

Frequencies

GnomAD3 genomes AF: 0.304 AC: 33957 AN: 111550 Hom.: 4105 Cov.: 24

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

GnomAD2 exomes AF: 0.310 AC: 36412 AN: 117570 AF XY: 0.300

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 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

African (AFR) AF: 0.256 AC: 5710 AN: 22281

American (AMR) AF: 0.475 AC: 9229 AN: 19420

Ashkenazi Jewish (ASJ) AF: 0.369 AC: 5720 AN: 15505

East Asian (EAS) AF: 0.791 AC: 19781 AN: 24994

South Asian (SAS) AF: 0.451 AC: 15731 AN: 34915

European-Finnish (FIN) AF: 0.210 AC: 7900 AN: 37588

Middle Eastern (MID) AF: 0.384 AC: 1437 AN: 3746

European-Non Finnish (NFE) AF: 0.252 AC: 200992 AN: 796608

Other (OTH) AF: 0.324 AC: 13374 AN: 41291

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

African (AFR) AF: 0.271 AC: 8314 AN: 30698

American (AMR) AF: 0.455 AC: 4803 AN: 10549

Ashkenazi Jewish (ASJ) AF: 0.408 AC: 1077 AN: 2641

East Asian (EAS) AF: 0.807 AC: 2844 AN: 3526

South Asian (SAS) AF: 0.530 AC: 1414 AN: 2666

European-Finnish (FIN) AF: 0.199 AC: 1199 AN: 6023

Middle Eastern (MID) AF: 0.344 AC: 73 AN: 212

European-Non Finnish (NFE) AF: 0.254 AC: 13478 AN: 53083

Other (OTH) AF: 0.344 AC: 528 AN: 1537

Alfa AF: 0.294 Hom.: 38614

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

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 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
PhyloP100		-0.62
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
PromoterAI		-0.13	Neutral
Varity_R		0.53
Mutation Taster		=169/31	polymorphism (auto)

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

Other links and lift over

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