chrX-12921293-C-A

Variant names:

• chrX-12921293-C-A
• rs3747414
• NM_138636.5:c.2253C>A

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.2253C>A​(p.Ile751Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.384 in 1,208,493 control chromosomes in the GnomAD database, including 63,258 homozygotes. There are 154,763 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (6242 hom., 13057 hem., cov: 23)
  • Exomes 𝑓: 0.38 (57016 hom. 141706 hem.)
• Consequence: TLR8 NM_138636.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.177
• Publications: 32 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=-0.52).
• BP6: Variant X-12921293-C-A is Benign according to our data. Variant chrX-12921293-C-A is described in ClinVar as Benign. ClinVar VariationId is 2688012.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.177 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR8	NM_138636.5	c.2253C>A	p.Ile751Ile	synonymous_variant	Exon 2 of 2	ENST00000218032.7	NP_619542.1
TLR8	NM_016610.4	c.2307C>A	p.Ile769Ile	synonymous_variant	Exon 3 of 3		NP_057694.2
TLR8-AS1	NR_030727.1	n.241-12960G>T		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR8	ENST00000218032.7	c.2253C>A	p.Ile751Ile	synonymous_variant	Exon 2 of 2	1	NM_138636.5	ENSP00000218032.7
TLR8	ENST00000311912.5	c.2307C>A	p.Ile769Ile	synonymous_variant	Exon 3 of 3	1		ENSP00000312082.5

Frequencies

GnomAD3 genomes AF: 0.393 AC: 43353 AN: 110447 Hom.: 6242 Cov.: 23

Gnomad AFR AF: 0.369

Gnomad AMI AF: 0.421

Gnomad AMR AF: 0.552

Gnomad ASJ AF: 0.372

Gnomad EAS AF: 0.800

Gnomad SAS AF: 0.608

Gnomad FIN AF: 0.351

Gnomad MID AF: 0.420

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.422

GnomAD2 exomes AF: 0.458 AC: 83370 AN: 182106 AF XY: 0.457

Gnomad AFR exome AF: 0.372

Gnomad AMR exome AF: 0.642

Gnomad ASJ exome AF: 0.362

Gnomad EAS exome AF: 0.802

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.341

Gnomad OTH exome AF: 0.422

GnomAD4 exome AF: 0.383 AC: 420144 AN: 1097992 Hom.: 57016 Cov.: 35 AF XY: 0.390 AC XY: 141706 AN XY: 363416

African (AFR) AF: 0.374 AC: 9877 AN: 26400

American (AMR) AF: 0.633 AC: 22261 AN: 35182

Ashkenazi Jewish (ASJ) AF: 0.364 AC: 7046 AN: 19381

East Asian (EAS) AF: 0.808 AC: 24396 AN: 30202

South Asian (SAS) AF: 0.603 AC: 32652 AN: 54132

European-Finnish (FIN) AF: 0.373 AC: 15087 AN: 40480

Middle Eastern (MID) AF: 0.432 AC: 1788 AN: 4135

European-Non Finnish (NFE) AF: 0.342 AC: 288223 AN: 841994

Other (OTH) AF: 0.408 AC: 18814 AN: 46086

GnomAD4 genome AF: 0.393 AC: 43380 AN: 110501 Hom.: 6242 Cov.: 23 AF XY: 0.398 AC XY: 13057 AN XY: 32797

African (AFR) AF: 0.369 AC: 11222 AN: 30399

American (AMR) AF: 0.552 AC: 5723 AN: 10360

Ashkenazi Jewish (ASJ) AF: 0.372 AC: 980 AN: 2636

East Asian (EAS) AF: 0.800 AC: 2792 AN: 3492

South Asian (SAS) AF: 0.606 AC: 1572 AN: 2594

European-Finnish (FIN) AF: 0.351 AC: 2043 AN: 5828

Middle Eastern (MID) AF: 0.429 AC: 93 AN: 217

European-Non Finnish (NFE) AF: 0.342 AC: 18031 AN: 52799

Other (OTH) AF: 0.426 AC: 641 AN: 1504

Alfa AF: 0.373 Hom.: 33505

Bravo AF: 0.413

EpiCase AF: 0.341

EpiControl AF: 0.352

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 72% of patients studied by a panel of primary immunodeficiencies. Number of patients: 68. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	2.7
DANN	Benign	0.58
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs3747414; hg19: chrX-12939412; COSMIC: COSV54316956;