4-38796673-T-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003263.4(TLR1):c.2159A>C(p.His720Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00674 in 1,614,174 control chromosomes in the GnomAD database, including 56 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (51 hom.)
• Consequence: TLR1 NM_003263.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.47

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008103281).
• BP6: Variant 4-38796673-T-G is Benign according to our data. Variant chr4-38796673-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 2654725.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 763 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR1	NM_003263.4	c.2159A>C	p.His720Pro	missense_variant	4/4	ENST00000308979.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR1	ENST00000308979.7	c.2159A>C	p.His720Pro	missense_variant	4/4	1	NM_003263.4	P1
TLR1	ENST00000502213.6	c.2159A>C	p.His720Pro	missense_variant	3/3	1		P1
TLR1	ENST00000505744.5	n.235+4184A>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 763 AN: 152168 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00352

Gnomad FIN AF: 0.00546

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00784

Gnomad OTH AF: 0.00526

GnomAD3 exomes AF: 0.00636 AC: 1600 AN: 251446 Hom.: 6 AF XY: 0.00648 AC XY: 880 AN XY: 135894

Gnomad AFR exome AF: 0.00141

Gnomad AMR exome AF: 0.00416

Gnomad ASJ exome AF: 0.00476

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00516

Gnomad FIN exome AF: 0.00614

Gnomad NFE exome AF: 0.00924

Gnomad OTH exome AF: 0.00685

GnomAD4 exome AF: 0.00692 AC: 10120 AN: 1461888 Hom.: 51 Cov.: 30 AF XY: 0.00699 AC XY: 5083 AN XY: 727244

Gnomad4 AFR exome AF: 0.00140

Gnomad4 AMR exome AF: 0.00458

Gnomad4 ASJ exome AF: 0.00421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00451

Gnomad4 FIN exome AF: 0.00648

Gnomad4 NFE exome AF: 0.00782

Gnomad4 OTH exome AF: 0.00528

GnomAD4 genome AF: 0.00502 AC: 764 AN: 152286 Hom.: 5 Cov.: 32 AF XY: 0.00442 AC XY: 329 AN XY: 74464

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00432

Gnomad4 ASJ AF: 0.00634

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00352

Gnomad4 FIN AF: 0.00546

Gnomad4 NFE AF: 0.00785

Gnomad4 OTH AF: 0.00521

Alfa AF: 0.00748 Hom.: 6

Bravo AF: 0.00468

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00272 AC: 12

ESP6500EA AF: 0.00779 AC: 67

ExAC AF: 0.00723 AC: 878

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00758

EpiControl AF: 0.00717

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

May 01, 2023

TLR1: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	21
Dann	Benign	0.97
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	-0.10
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.89	D;.
MetaRNN	Benign	0.0081	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	2.9	M;M
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Benign	0.11
Sift	Uncertain	0.0090	D;D
Sift4G	Benign	0.25	T;T
Polyphen		0.20	B;B
Vest4		0.54
MVP		0.68
MPC		0.35
ClinPred		0.078	T
GERP RS		4.0
Varity_R		0.84
gMVP		0.25

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: rs113706342; hg19: chr4-38798294;