4-38827699-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006068.5(TLR6):c.1775G>T(p.Gly592Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00287 in 1,613,936 control chromosomes in the GnomAD database, including 97 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0033 (14 hom., cov: 32)
  • Exomes 𝑓: 0.0028 (83 hom.)
• Consequence: TLR6 NM_006068.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.525

Genes affected

TLR6 (HGNC:16711): (toll like receptor 6) 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 receptor functionally interacts with toll-like receptor 2 to mediate cellular response to bacterial lipoproteins. A Ser249Pro polymorphism in the extracellular domain of the encoded protein may be associated with an increased of asthma is some populations.[provided by RefSeq, Jan 2011]

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022054613).
• BP6: Variant 4-38827699-C-A is Benign according to our data. Variant chr4-38827699-C-A is described in ClinVar as [Benign]. Clinvar id is 773694.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00327 (498/152264) while in subpopulation EAS AF= 0.0392 (203/5172). AF 95% confidence interval is 0.0348. There are 14 homozygotes in gnomad4. There are 307 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR6	NM_006068.5	c.1775G>T	p.Gly592Val	missense_variant	2/2	ENST00000508254.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR6	ENST00000508254.6	c.1775G>T	p.Gly592Val	missense_variant	2/2	1	NM_006068.5	P1
TLR6	ENST00000381950.2	c.1775G>T	p.Gly592Val	missense_variant	3/3			P1
TLR1	ENST00000506146.5	c.-352-22506G>T		intron_variant		4

Frequencies

GnomAD3 genomes AF: 0.00327 AC: 497 AN: 152146 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0390

Gnomad SAS AF: 0.0292

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00578 AC: 1454 AN: 251450 Hom.: 32 AF XY: 0.00648 AC XY: 881 AN XY: 135908

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0375

Gnomad SAS exome AF: 0.0211

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000264

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00282 AC: 4127 AN: 1461672 Hom.: 83 Cov.: 36 AF XY: 0.00344 AC XY: 2499 AN XY: 727158

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0421

Gnomad4 SAS exome AF: 0.0220

Gnomad4 FIN exome AF: 0.0000749

Gnomad4 NFE exome AF: 0.000155

Gnomad4 OTH exome AF: 0.00422

GnomAD4 genome AF: 0.00327 AC: 498 AN: 152264 Hom.: 14 Cov.: 32 AF XY: 0.00412 AC XY: 307 AN XY: 74442

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.00510

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0392

Gnomad4 SAS AF: 0.0291

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000279

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.000700 Hom.: 1

Bravo AF: 0.00241

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.00589 AC: 715

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	0.087
Dann	Benign	0.70
DEOGEN2	Benign	0.044	T;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.020	N
LIST_S2	Benign	0.72	T;.
MetaRNN	Benign	0.0022	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.43	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	2.1	N;N
REVEL	Benign	0.066
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	B;B
Vest4		0.11
MVP		0.20
MPC		0.19
ClinPred		0.0066	T
GERP RS		-4.9
Varity_R		0.046
gMVP		0.46

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: rs75244616; hg19: chr4-38829320; COSMIC: COSV67935003; COSMIC: COSV67935003;