4-38828729-A-G

Variant names:

• chr4-38828729-A-G
• rs5743810
• NM_006068.5:c.745T>C
• TLR6 p.Ser249Pro

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-5 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -5 classification points (ACGS-UK Somatic Oncogenicity v2025). B1_StrongB3_Supporting

The NM_006068.5(TLR6):c.745T>C (p.Ser249Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a cumulative frequency of 0.625 (AC=1,009,123) in the gnomAD database across 1,613,632 control chromosomes, including 334,649 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.991. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S249A: protective (ClinVar VariationId 1710535, 0 stars) The variant has been observed in cBioPortal in 3 samples across 3 studies and 1 cancer type; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.72 (42057 hom., cov: 32)
  • Exomes 𝑓: 0.62 (292592 hom.)
• Consequence: TLR6 NM_006068.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.928
• Publications: 33 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]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -5 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	B1High frequency in general population		GnomAD effective popmax AF >1% — B1 stand-alone benign; GnomAD effective popmax AF = 0.991 — exceeds 1% threshold (B1 applied)
	B3Computational evidence does not support deleterious effect		Computational evidence does not support a deleterious effect; Missense variant — primary computational scorer does not support an oncogenic/deleterious effect; supports B3

Variant Effect in Transcripts

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

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TLR6 NM_006068.5	MANE Select	c.745T>C p.Ser249Pro	missense	Exon 2 of 2	Prot: NP_006059.2
	TLR6 NM_001394553.1		c.745T>C p.Ser249Pro	missense	Exon 2 of 2	Prot: NP_001381482.1 UniProt:

TLR6 NM_006068.5

MANE Select

HGVSc / HGVSpc.745T>Cp.Ser249Pro

Exon rankExon 2 of 2

missense

Prot: NP_006059.2

TLR6 NM_001394553.1

HGVSc / HGVSpc.745T>Cp.Ser249Pro

Exon rankExon 2 of 2

missense

Prot: NP_001381482.1UniProt: Q9Y2C9-1

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	TLR6 ENST00000508254.6	TSL:1MANE Select	c.745T>C p.Ser249Pro	missense	Exon 2 of 2	Prot: ENSP00000424718.2 UniProt:
	TLR6 ENST00000381950.2	TSL:6	c.745T>C p.Ser249Pro	missense	Exon 3 of 3	Prot: ENSP00000371376.1 UniProt:
	TLR6 ENST00000966018.1		c.745T>C p.Ser249Pro	missense	Exon 2 of 2	Prot: ENSP00000636077.1 UniProt:

TLR6 ENST00000508254.6

TSL:1MANE Select

HGVSc / HGVSpc.745T>Cp.Ser249Pro

Exon rankExon 2 of 2

missense

Prot: ENSP00000424718.2UniProt: Q9Y2C9-1

TLR6 ENST00000381950.2

TSL:6

HGVSc / HGVSpc.745T>Cp.Ser249Pro

Exon rankExon 3 of 3

missense

Prot: ENSP00000371376.1UniProt: Q9Y2C9-1

TLR6 ENST00000966018.1

HGVSc / HGVSpc.745T>Cp.Ser249Pro

Exon rankExon 2 of 2

missense

Prot: ENSP00000636077.1UniProt: Q9Y2C9-1

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.722	AC:109767	Hom:41993	AN:152042	Cov:32
GnomAD2 exomes	AF: 0.729	AC:183018	Hom:	AN:250972	Cov:
GnomAD4 exome	AF: 0.615	AC:899232	Hom:292592	AN:1461472	Cov:49
GnomAD4 genome	AF: 0.722	AC:109891	Hom:42057	AN:152160	Cov:32
TOPMed (Bravo)	AF: 0.748	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.645	AC:237924	Hom:79970	AN:369150	Cov:
Local & regional cohorts 9 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.763	AC:1786	Hom:692	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.998	AC:	Hom:	AN:	Cov:
Denmark Genome	AF: 0.607	AC:182	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.692	AC:8994	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.969	AC:3370	Hom:	AN:3478	Cov:
Qatari Genome	AF: 0.900	AC:1807	Hom:	AN:2008	Cov:
Turkish Variome	AF: 0.767	AC:5153	Hom:1999	AN:6718	Cov:
UK10K	AF: 0.563	AC:4255	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.999	AC:8951	Hom:4471	AN:8960	Cov:

Showing 15 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.562 *	5407	9616	0.559 *	5830	10424
BipEx(Bipolar disorder (including schizoaffective))	0.570	16190	28420	0.573	16539	28844
Epi25(Epilepsy)	0.660	27676	41958	0.651	43566	66886
SCHEMA(Schizophrenia)	0.736	108100	146928	0.701	177305	252978

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	16
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	8.5
DANN	Benign	0.62
DEOGEN2	Benign	0.062	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.013	N
FuncVEP CTI	Benign	0.011
GPN-Star LLR	N/A	7.0
GPN-Star score	N/A	2.6
LIST_S2	Benign	0.15	T
MetaRNN	Benign	0.0000012	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	100/0	polymorphism (auto)
MutationAssessor	Benign	-1.3	N
PhyloP100	Benign	0.93
popEVE	Benign	-2.4
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.039
Sift	Benign	0.45	T
Sift4G	Benign	0.39	T
Varity_R	N/A	0.029
VESM-3B	Benign	-4.6

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs5743810;

hg19: chr4-38830350;

COSMIC: COSV67935256;

COSMIC: COSV67935256;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar