4-38798089-T-C

Variant names:

• chr4-38798089-T-C
• rs4833095
• NM_003263.4:c.743A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_003263.4(TLR1):​c.743A>G​(p.Asn248Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,613,238 control chromosomes in the GnomAD database, including 90,036 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.44 (19255 hom., cov: 32)
  • Exomes 𝑓: 0.27 (70781 hom.)
• Consequence: TLR1 NM_003263.4 missense
• Clinical Significance: Benign; risk factor no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: -0.964
• Publications: 306 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.6334178E-6).
• BP6: Variant 4-38798089-T-C is Benign according to our data. Variant chr4-38798089-T-C is described in ClinVar as Benign|risk_factor. ClinVar VariationId is 8361.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.784 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003263.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR1	NM_003263.4	MANE Select	c.743A>G	p.Asn248Ser	missense	Exon 4 of 4	NP_003254.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR1	ENST00000308979.7	TSL:1 MANE Select	c.743A>G	p.Asn248Ser	missense	Exon 4 of 4	ENSP00000354932.2
	TLR1	ENST00000502213.7	TSL:1	c.743A>G	p.Asn248Ser	missense	Exon 4 of 4	ENSP00000421259.1
	TLR1	ENST00000505744.6	TSL:3	n.235+2768A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.436 AC: 66260 AN: 152006 Hom.: 19203 Cov.: 32

Gnomad AFR AF: 0.791

Gnomad AMI AF: 0.318

Gnomad AMR AF: 0.503

Gnomad ASJ AF: 0.418

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.490

Gnomad FIN AF: 0.114

Gnomad MID AF: 0.566

Gnomad NFE AF: 0.239

Gnomad OTH AF: 0.483

GnomAD2 exomes AF: 0.381 AC: 95308 AN: 250080 AF XY: 0.374

Gnomad AFR exome AF: 0.801

Gnomad AMR exome AF: 0.517

Gnomad ASJ exome AF: 0.414

Gnomad EAS exome AF: 0.595

Gnomad FIN exome AF: 0.120

Gnomad NFE exome AF: 0.266

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.273 AC: 399521 AN: 1461114 Hom.: 70781 Cov.: 36 AF XY: 0.279 AC XY: 202717 AN XY: 726712

African (AFR) AF: 0.808 AC: 27057 AN: 33472

American (AMR) AF: 0.513 AC: 22893 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.412 AC: 10764 AN: 26128

East Asian (EAS) AF: 0.634 AC: 25154 AN: 39688

South Asian (SAS) AF: 0.481 AC: 41478 AN: 86210

European-Finnish (FIN) AF: 0.124 AC: 6623 AN: 53380

Middle Eastern (MID) AF: 0.532 AC: 3067 AN: 5768

European-Non Finnish (NFE) AF: 0.218 AC: 242642 AN: 1111434

Other (OTH) AF: 0.329 AC: 19843 AN: 60372

GnomAD4 genome AF: 0.436 AC: 66372 AN: 152124 Hom.: 19255 Cov.: 32 AF XY: 0.435 AC XY: 32398 AN XY: 74396

African (AFR) AF: 0.791 AC: 32847 AN: 41502

American (AMR) AF: 0.503 AC: 7683 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.418 AC: 1448 AN: 3466

East Asian (EAS) AF: 0.597 AC: 3086 AN: 5168

South Asian (SAS) AF: 0.490 AC: 2364 AN: 4824

European-Finnish (FIN) AF: 0.114 AC: 1212 AN: 10608

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.239 AC: 16245 AN: 67960

Other (OTH) AF: 0.486 AC: 1029 AN: 2116

Alfa AF: 0.331 Hom.: 41573

Bravo AF: 0.480

TwinsUK AF: 0.226 AC: 837

ALSPAC AF: 0.248 AC: 954

ESP6500AA AF: 0.777 AC: 3424

ESP6500EA AF: 0.249 AC: 2141

ExAC AF: 0.393 AC: 47671

Asia WGS AF: 0.564 AC: 1960 AN: 3478

ClinVar

Significance: Benign; risk factor

Submissions summary: Benign:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

TLR1-related disorder Benign:1

Oct 18, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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).

Leprosy, susceptibility to, 5 Other:1

Jun 15, 2009

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.27
DANN	Benign	0.43
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.050	N
LIST_S2	Benign	0.060	T
MetaRNN	Benign	0.0000026	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.96
PrimateAI	Benign	0.23	T
PROVEAN	Uncertain	-2.5	D
REVEL	Benign	0.028
Sift	Benign	0.17	T
Sift4G	Benign	0.25	T
Polyphen		0.0010	B
Vest4		0.016
MPC		0.053
ClinPred		0.0096	T
GERP RS		-3.2
Varity_R		0.11
gMVP		0.14
Mutation Taster		=93/7	polymorphism (auto)

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: rs4833095; hg19: chr4-38799710; COSMIC: COSV58303357; COSMIC: COSV58303357;