4-38774173-A-G

Position:

• chr4-38774173-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_030956.4(TLR10):​c.1418T>C​(p.Ile473Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0266 in 1,611,554 control chromosomes in the GnomAD database, including 681 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.025 (64 hom., cov: 32)
  • Exomes 𝑓: 0.027 (617 hom.)
• Consequence: TLR10 NM_030956.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.99

Genes affected

TLR10 (HGNC:15634): (toll like receptor 10) 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 most highly expressed in lymphoid tissues such as spleen, lymph node, thymus, and tonsil. Multiple alternatively spliced transcript variants which encode different protein isoforms have been found for this gene. [provided by RefSeq, Aug 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00271371).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0245 (3734/152330) while in subpopulation AMR AF= 0.0439 (671/15294). AF 95% confidence interval is 0.0411. There are 64 homozygotes in gnomad4. There are 1738 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 64 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TLR10	NM_030956.4	c.1418T>C	p.Ile473Thr	missense_variant	4/4	ENST00000308973.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TLR10	ENST00000308973.9	c.1418T>C	p.Ile473Thr	missense_variant	4/4	5	NM_030956.4	P1

Frequencies

GnomAD3 genomes AF: 0.0246 AC: 3737 AN: 152212 Hom.: 64 Cov.: 32

Gnomad AFR AF: 0.00507

Gnomad AMI AF: 0.107

Gnomad AMR AF: 0.0439

Gnomad ASJ AF: 0.0617

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0145

Gnomad FIN AF: 0.00866

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0334

Gnomad OTH AF: 0.0421

GnomAD3 exomes AF: 0.0267 AC: 6623 AN: 248226 Hom.: 143 AF XY: 0.0280 AC XY: 3754 AN XY: 134132

Gnomad AFR exome AF: 0.00416

Gnomad AMR exome AF: 0.0290

Gnomad ASJ exome AF: 0.0556

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0175

Gnomad FIN exome AF: 0.00865

Gnomad NFE exome AF: 0.0364

Gnomad OTH exome AF: 0.0357

GnomAD4 exome AF: 0.0268 AC: 39053 AN: 1459224 Hom.: 617 Cov.: 35 AF XY: 0.0269 AC XY: 19522 AN XY: 725674

Gnomad4 AFR exome AF: 0.00438

Gnomad4 AMR exome AF: 0.0306

Gnomad4 ASJ exome AF: 0.0576

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0166

Gnomad4 FIN exome AF: 0.00863

Gnomad4 NFE exome AF: 0.0290

Gnomad4 OTH exome AF: 0.0273

GnomAD4 genome AF: 0.0245 AC: 3734 AN: 152330 Hom.: 64 Cov.: 32 AF XY: 0.0233 AC XY: 1738 AN XY: 74502

Gnomad4 AFR AF: 0.00505

Gnomad4 AMR AF: 0.0439

Gnomad4 ASJ AF: 0.0617

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0143

Gnomad4 FIN AF: 0.00866

Gnomad4 NFE AF: 0.0333

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0351 Hom.: 286

Bravo AF: 0.0269

TwinsUK AF: 0.0291 AC: 108

ALSPAC AF: 0.0285 AC: 110

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0373 AC: 321

ExAC AF: 0.0272 AC: 3307

Asia WGS AF: 0.00895 AC: 31 AN: 3478

EpiCase AF: 0.0436

EpiControl AF: 0.0453

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.37	T;T;T;T;T;T
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.17
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.56	.;.;.;T;.;.
MetaRNN	Benign	0.0027	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M;M;M;M;M
MutationTaster	Benign	0.74	N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-3.5	D;.;D;.;D;D
REVEL	Benign	0.086
Sift	Uncertain	0.0020	D;.;D;.;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D
Polyphen		0.30	B;B;B;B;B;B
Vest4		0.52
MPC		0.079
ClinPred		0.060	T
GERP RS		4.1
Varity_R		0.33
gMVP		0.42

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: rs11466657; hg19: chr4-38775794;