4-38796894-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003263.4(TLR1):c.1938C>T(p.His646=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,614,132 control chromosomes in the GnomAD database, including 152 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (25 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (127 hom.)
• Consequence: TLR1 NM_003263.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.96

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 4-38796894-G-A is Benign according to our data. Variant chr4-38796894-G-A is described in ClinVar as [Benign]. Clinvar id is 779876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.96 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR1	NM_003263.4	c.1938C>T	p.His646=	synonymous_variant	4/4	ENST00000308979.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR1	ENST00000308979.7	c.1938C>T	p.His646=	synonymous_variant	4/4	1	NM_003263.4	P1
TLR1	ENST00000502213.6	c.1938C>T	p.His646=	synonymous_variant	3/3	1		P1
TLR1	ENST00000505744.5	n.235+3963C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00408 AC: 621 AN: 152124 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0982

Gnomad SAS AF: 0.00664

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00862 AC: 2166 AN: 251402 Hom.: 95 AF XY: 0.00784 AC XY: 1065 AN XY: 135860

Gnomad AFR exome AF: 0.000738

Gnomad AMR exome AF: 0.00182

Gnomad ASJ exome AF: 0.00317

Gnomad EAS exome AF: 0.101

Gnomad SAS exome AF: 0.00248

Gnomad FIN exome AF: 0.000508

Gnomad NFE exome AF: 0.000572

Gnomad OTH exome AF: 0.00717

GnomAD4 exome AF: 0.00283 AC: 4130 AN: 1461890 Hom.: 127 Cov.: 30 AF XY: 0.00275 AC XY: 2003 AN XY: 727246

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00275

Gnomad4 EAS exome AF: 0.0775

Gnomad4 SAS exome AF: 0.00206

Gnomad4 FIN exome AF: 0.000655

Gnomad4 NFE exome AF: 0.000201

Gnomad4 OTH exome AF: 0.00755

GnomAD4 genome AF: 0.00408 AC: 621 AN: 152242 Hom.: 25 Cov.: 32 AF XY: 0.00469 AC XY: 349 AN XY: 74428

Gnomad4 AFR AF: 0.000843

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0982

Gnomad4 SAS AF: 0.00685

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000718 Hom.: 0

Bravo AF: 0.00465

Asia WGS AF: 0.0530 AC: 183 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

TLR1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 15, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.14
Dann	Benign	0.30

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: rs72493538; hg19: chr4-38798515; COSMIC: COSV58303194; COSMIC: COSV58303194;