4-38828211-T-G

Variant names:

• chr4-38828211-T-G
• rs3775073
• NM_006068.5:c.1263A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006068.5(TLR6):​c.1263A>C​(p.Lys421Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TLR6 NM_006068.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.978
• Publications: 48 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05583757).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006068.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR6	NM_006068.5	MANE Select	c.1263A>C	p.Lys421Asn	missense	Exon 2 of 2	NP_006059.2
	TLR6	NM_001394553.1		c.1263A>C	p.Lys421Asn	missense	Exon 2 of 2	NP_001381482.1	Q9Y2C9-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR6	ENST00000508254.6	TSL:1 MANE Select	c.1263A>C	p.Lys421Asn	missense	Exon 2 of 2	ENSP00000424718.2	Q9Y2C9-1
	TLR6	ENST00000381950.2	TSL:6	c.1263A>C	p.Lys421Asn	missense	Exon 3 of 3	ENSP00000371376.1	Q9Y2C9-1
	TLR6	ENST00000966018.1		c.1263A>C	p.Lys421Asn	missense	Exon 2 of 2	ENSP00000636077.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 49

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 34762

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	2.3
DANN	Benign	0.90
DEOGEN2	Benign	0.066	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0034	T
MetaRNN	Benign	0.056	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.47	N
PhyloP100		-0.98
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.55	N
REVEL	Benign	0.0050
Sift	Benign	0.15	T
Sift4G	Benign	0.25	T
Polyphen		0.0	B
Vest4		0.034
MutPred		0.42		Loss of ubiquitination at K421 (P = 0.0081)
MVP		0.17
MPC		0.18
ClinPred		0.064	T
GERP RS		-2.5
Varity_R		0.055
gMVP		0.23
Mutation Taster		=95/5	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

Other links and lift over

dbSNP: rs3775073; hg19: chr4-38829832;