X-12919601-C-T

Variant names:

• chrX-12919601-C-T
• rs5744079
• NM_138636.5:c.561C>T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_138636.5(TLR8):​c.561C>T​(p.Cys187Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00228 in 1,206,965 control chromosomes in the GnomAD database, including 40 homozygotes. There are 723 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (15 hom., 353 hem., cov: 23)
  • Exomes 𝑓: 0.0013 (25 hom. 370 hem.)
• Consequence: TLR8 NM_138636.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.521

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant X-12919601-C-T is Benign according to our data. Variant chrX-12919601-C-T is described in ClinVar as [Benign]. Clinvar id is 784429.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.521 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0117 (1309/111805) while in subpopulation AFR AF= 0.0402 (1238/30773). AF 95% confidence interval is 0.0384. There are 15 homozygotes in gnomad4. There are 353 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR8	NM_138636.5	c.561C>T	p.Cys187Cys	synonymous_variant	Exon 2 of 2	ENST00000218032.7	NP_619542.1
TLR8	NM_016610.4	c.615C>T	p.Cys205Cys	synonymous_variant	Exon 3 of 3		NP_057694.2
TLR8-AS1	NR_030727.1	n.241-11268G>A		intron_variant	Intron 2 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR8	ENST00000218032.7	c.561C>T	p.Cys187Cys	synonymous_variant	Exon 2 of 2	1	NM_138636.5	ENSP00000218032.7
TLR8	ENST00000311912.5	c.615C>T	p.Cys205Cys	synonymous_variant	Exon 3 of 3	1		ENSP00000312082.5

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1309 AN: 111754 Hom.: 15 Cov.: 23 AF XY: 0.0105 AC XY: 355 AN XY: 33970

Gnomad AFR AF: 0.0403

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00494

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00417

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.0106

GnomAD3 exomes AF: 0.00354 AC: 630 AN: 178165 Hom.: 15 AF XY: 0.00248 AC XY: 158 AN XY: 63691

Gnomad AFR exome AF: 0.0421

Gnomad AMR exome AF: 0.00238

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000572

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000747

Gnomad OTH exome AF: 0.00251

GnomAD4 exome AF: 0.00132 AC: 1445 AN: 1095160 Hom.: 25 Cov.: 32 AF XY: 0.00103 AC XY: 370 AN XY: 360958

Gnomad4 AFR exome AF: 0.0424

Gnomad4 AMR exome AF: 0.00314

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000331

Gnomad4 SAS exome AF: 0.000619

Gnomad4 FIN exome AF: 0.0000494

Gnomad4 NFE exome AF: 0.0000523

Gnomad4 OTH exome AF: 0.00300

GnomAD4 genome AF: 0.0117 AC: 1309 AN: 111805 Hom.: 15 Cov.: 23 AF XY: 0.0104 AC XY: 353 AN XY: 34031

Gnomad4 AFR AF: 0.0402

Gnomad4 AMR AF: 0.00494

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000371

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.0105

Alfa AF: 0.00560 Hom.: 11

Bravo AF: 0.0138

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 16, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.53
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs5744079; hg19: chrX-12937720;