Genetic Variant TLR1:c.*5568T>C (chr4-38790903-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The ENST00000502213.7(TLR1):c.*5568T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.316 in 152,148 control chromosomes in the GnomAD database, including 9,021 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.32 ( 9021 hom., cov: 32)

Exomes 𝑓: 0.25 ( 0 hom. )

Consequence

TLR1
ENST00000502213.7 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -3.83

Publications

45 publications found

Variant links:

Genes affected

TLR1 (HGNC:11847): (toll like receptor 1) 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 ubiquitously expressed, and at higher levels than other TLR genes. Different length transcripts presumably resulting from use of alternative polyadenylation site, and/or from alternative splicing, have been noted for this gene. [provided by RefSeq, Jul 2008]

TLR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.01).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.498 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank
TLR1	XR_007057953.1 link	n.2987T>C	non_coding_transcript_exon_variant	Exon 4 of 4
TLR1	XR_007057954.1 link	n.2895T>C	non_coding_transcript_exon_variant	Exon 3 of 3
TLR1	XR_925165.3 link	n.3064T>C	non_coding_transcript_exon_variant	Exon 5 of 5

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	Protein	UniProt
TLR1	ENST00000502213.7 link	c.*5568T>C	3_prime_UTR_variant	Exon 4 of 4	1	ENSP00000421259.1	Q15399
TLR1	ENST00000505744.6 link	n.564T>C	non_coding_transcript_exon_variant	Exon 4 of 4	3
TLR1	ENST00000510552.2 link	n.459T>C	non_coding_transcript_exon_variant	Exon 3 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.315

AC:

47933

AN:

152026

Hom.:

8993

Cov.:

show subpopulations

Gnomad AFR

AF:

0.503

Gnomad AMI

AF:

0.292

Gnomad AMR

AF:

0.279

Gnomad ASJ

AF:

0.388

Gnomad EAS

AF:

0.400

Gnomad SAS

AF:

0.325

Gnomad FIN

AF:

0.105

Gnomad MID

AF:

0.494

Gnomad NFE

AF:

0.229

Gnomad OTH

AF:

0.367

GnomAD4 exome

AF:

0.250

AC:

AN:

Hom.:

Cov.:

AF XY:

0.250

AC XY:

AN XY:

show subpopulations

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

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.250

AC:

AN:

Other (OTH)

AC:

AN:

⚠️ 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: 0.275

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.316

AC:

48011

AN:

152144

Hom.:

9021

Cov.:

AF XY:

0.311

AC XY:

23150

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.503

AC:

20886

AN:

41482

American (AMR)

AF:

0.279

AC:

4263

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.388

AC:

1347

AN:

3470

East Asian (EAS)

AF:

0.400

AC:

2074

AN:

5180

South Asian (SAS)

AF:

0.326

AC:

1571

AN:

4824

European-Finnish (FIN)

AF:

0.105

AC:

1112

AN:

10610

Middle Eastern (MID)

AF:

0.497

AC:

145

AN:

292

European-Non Finnish (NFE)

AF:

0.229

AC:

15576

AN:

67990

Other (OTH)

AF:

0.366

AC:

772

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1561

3121

4682

6242

7803

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

464

928

1392

1856

2320

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.272

Hom.:

4445

Bravo

AF:

0.339

Asia WGS

AF:

0.340

AC:

1182

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.085

(source)

DANN

Benign

0.35

PhyloP100

-3.8

Splicing

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over