NM_138636.5:c.354C>T

Variant names:

• chrX-12919394-C-T
• rs2159377
• NM_138636.5:c.354C>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.354C>T​(p.Asp118Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 1,208,912 control chromosomes in the GnomAD database, including 22,885 homozygotes. There are 87,606 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.21 (2196 hom., 7023 hem., cov: 22)
  • Exomes 𝑓: 0.21 (20689 hom. 80583 hem.)
• Consequence: TLR8 NM_138636.5 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.289
• Publications: 34 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=-0.75).
• BP6: Variant X-12919394-C-T is Benign according to our data. Variant chrX-12919394-C-T is described in ClinVar as Benign. ClinVar VariationId is 2688225.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.289 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.724 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR8	NM_138636.5	c.354C>T	p.Asp118Asp	synonymous_variant	Exon 2 of 2	ENST00000218032.7	NP_619542.1
TLR8	NM_016610.4	c.408C>T	p.Asp136Asp	synonymous_variant	Exon 3 of 3		NP_057694.2
TLR8-AS1	NR_030727.1	n.241-11061G>A		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR8	ENST00000218032.7	c.354C>T	p.Asp118Asp	synonymous_variant	Exon 2 of 2	1	NM_138636.5	ENSP00000218032.7
TLR8	ENST00000311912.5	c.408C>T	p.Asp136Asp	synonymous_variant	Exon 3 of 3	1		ENSP00000312082.5

Frequencies

GnomAD3 genomes AF: 0.208 AC: 23049 AN: 110957 Hom.: 2196 Cov.: 22

Gnomad AFR AF: 0.150

Gnomad AMI AF: 0.379

Gnomad AMR AF: 0.305

Gnomad ASJ AF: 0.210

Gnomad EAS AF: 0.748

Gnomad SAS AF: 0.461

Gnomad FIN AF: 0.139

Gnomad MID AF: 0.232

Gnomad NFE AF: 0.178

Gnomad OTH AF: 0.226

GnomAD2 exomes AF: 0.277 AC: 50483 AN: 182117 AF XY: 0.285

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.760

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.213 AC: 233349 AN: 1097902 Hom.: 20689 Cov.: 33 AF XY: 0.222 AC XY: 80583 AN XY: 363326

African (AFR) AF: 0.148 AC: 3897 AN: 26396

American (AMR) AF: 0.346 AC: 12173 AN: 35177

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 3830 AN: 19375

East Asian (EAS) AF: 0.748 AC: 22606 AN: 30202

South Asian (SAS) AF: 0.454 AC: 24574 AN: 54102

European-Finnish (FIN) AF: 0.150 AC: 6065 AN: 40502

Middle Eastern (MID) AF: 0.219 AC: 904 AN: 4130

European-Non Finnish (NFE) AF: 0.176 AC: 148308 AN: 841935

Other (OTH) AF: 0.239 AC: 10992 AN: 46083

GnomAD4 genome AF: 0.208 AC: 23059 AN: 111010 Hom.: 2196 Cov.: 22 AF XY: 0.211 AC XY: 7023 AN XY: 33242

African (AFR) AF: 0.150 AC: 4596 AN: 30549

American (AMR) AF: 0.305 AC: 3188 AN: 10437

Ashkenazi Jewish (ASJ) AF: 0.210 AC: 552 AN: 2632

East Asian (EAS) AF: 0.748 AC: 2617 AN: 3500

South Asian (SAS) AF: 0.459 AC: 1208 AN: 2631

European-Finnish (FIN) AF: 0.139 AC: 824 AN: 5908

Middle Eastern (MID) AF: 0.250 AC: 54 AN: 216

European-Non Finnish (NFE) AF: 0.178 AC: 9416 AN: 52954

Other (OTH) AF: 0.231 AC: 348 AN: 1508

Alfa AF: 0.196 Hom.: 21548

Bravo AF: 0.223

EpiCase AF: 0.189

EpiControl AF: 0.192

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 33% of patients studied by a panel of primary immunodeficiencies. Number of patients: 31. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.016
DANN	Benign	0.26
PhyloP100		-0.29
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: rs2159377; hg19: chrX-12937513; COSMIC: COSV54321256;