Genetic Variant TLR10:p.Arg799Leu (chr4-38773195-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_030956.4(TLR10):c.2396G>T(p.Arg799Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000713 in 1,402,554 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R799Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

TLR10
NM_030956.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.865

Publications

17 publications found

Variant links:

Genes affected

TLR10 (HGNC:15634): (toll like receptor 10) 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 most highly expressed in lymphoid tissues such as spleen, lymph node, thymus, and tonsil. Multiple alternatively spliced transcript variants which encode different protein isoforms have been found for this gene. [provided by RefSeq, Aug 2010]

TLR10 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.091046005).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030956.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLR10	NM_030956.4	MANE Select	c.2396G>T	p.Arg799Leu	missense	Exon 4 of 4	NP_112218.2	Q9BXR5
TLR10	NM_001017388.3		c.2396G>T	p.Arg799Leu	missense	Exon 2 of 2	NP_001017388.1	Q9BXR5
TLR10	NM_001195106.2		c.2396G>T	p.Arg799Leu	missense	Exon 3 of 3	NP_001182035.1	Q9BXR5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TLR10	ENST00000308973.9	TSL:5 MANE Select	c.2396G>T	p.Arg799Leu	missense	Exon 4 of 4	ENSP00000308925.4	Q9BXR5
TLR10	ENST00000361424.6	TSL:1	c.2396G>T	p.Arg799Leu	missense	Exon 2 of 2	ENSP00000354459.2	Q9BXR5
TLR10	ENST00000506111.1	TSL:1	c.2396G>T	p.Arg799Leu	missense	Exon 2 of 2	ENSP00000421483.1	Q9BXR5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.13e-7

AC:

AN:

1402554

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

693044

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31238

American (AMR)

AF:

0.00

AC:

AN:

34100

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21862

East Asian (EAS)

AF:

0.00

AC:

AN:

39416

South Asian (SAS)

AF:

0.0000135

AC:

AN:

74090

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50948

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5464

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1087564

Other (OTH)

AF:

0.00

AC:

AN:

57872

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.64

CADD

Benign

0.42

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.027

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.082

LIST_S2

Benign

0.80

M_CAP

Benign

0.0044

MetaRNN

Benign

0.091

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.8

PhyloP100

-0.86

PrimateAI

Benign

0.17

PROVEAN

Benign

-0.65

REVEL

Benign

0.033

Sift

Uncertain

0.021

Sift4G

Benign

0.094

Polyphen

0.36

Vest4

0.20

MutPred

0.16

Gain of glycosylation at S804 (P = 0.0209)

MVP

0.15

MPC

0.091

ClinPred

0.097

GERP RS

-1.6

Varity_R

0.059

gMVP

0.23

Mutation Taster

=99/1

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over