chrX-12885857-C-A

Variant names:

• chrX-12885857-C-A
• rs201467088
• NM_016562.4:c.349C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_016562.4(TLR7):​c.349C>A​(p.Gln117Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00001 in 1,098,219 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.000010 (0 hom. 5 hem.)
• Consequence: TLR7 NM_016562.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0540

Genes affected

TLR7 (HGNC:15631): (toll like receptor 7) 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. The human TLR family comprises 11 members. 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. For the recognition of structural components in foreign microorganisms, the various TLRs exhibit different patterns of expression as well; in this way for example, TLR-3, -7, and -8 are essential in the recognition of single-stranded RNA viruses. TLR7 senses single-stranded RNA oligonucleotides containing guanosine- and uridine-rich sequences from RNA viruses, a recognition occuring in the endosomes of plasmacytoid dendritic cells and B cells. This gene is predominantly expressed in lung, placenta, and spleen, and is phylogenetically related and lies in close proximity to another family member, TLR8, on chromosome X. [provided by RefSeq, Aug 2020]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046556383).
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR7	NM_016562.4	c.349C>A	p.Gln117Lys	missense_variant	Exon 3 of 3	ENST00000380659.4	NP_057646.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR7	ENST00000380659.4	c.349C>A	p.Gln117Lys	missense_variant	Exon 3 of 3	1	NM_016562.4	ENSP00000370034.3

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD2 exomes AF: 0.0000273 AC: 5 AN: 183242 AF XY: 0.0000443

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000367

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 11 AN: 1098219 Hom.: 0 Cov.: 32 AF XY: 0.0000138 AC XY: 5 AN XY: 363573

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 26403

Gnomad4 AMR exome AF: 0.0000284 AC: 1 AN: 35206

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 19384

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 30206

Gnomad4 SAS exome AF: 0.0000185 AC: 1 AN: 54147

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 40532

Gnomad4 NFE exome AF: 0.00000594 AC: 5 AN: 842108

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 46096

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.349C>A (p.Q117K) alteration is located in exon 3 (coding exon 2) of the TLR7 gene. This alteration results from a C to A substitution at nucleotide position 349, causing the glutamine (Q) at amino acid position 117 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 117 of the TLR7 protein (p.Gln117Lys). This variant is present in population databases (rs201467088, gnomAD 0.005%). This variant has not been reported in the literature in individuals affected with TLR7-related conditions. ClinVar contains an entry for this variant (Variation ID: 2473048). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.8
DANN	Benign	0.54
DEOGEN2	Benign	0.092	T
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.0062	T
MetaRNN	Benign	0.047	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	-0.035	N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.0080
Sift	Benign	0.32	T
Sift4G	Benign	0.93	T
Polyphen		0.0	B
Vest4		0.069
MutPred		0.45		Gain of catalytic residue at Q117 (P = 0.0057);
MVP		0.30
MPC		0.88
ClinPred		0.043	T
GERP RS		1.6
Varity_R		0.11
gMVP		0.39
Mutation Taster		=96/4	polymorphism

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: rs201467088; hg19: chrX-12903976;