4-38773268-T-C

Position:

• chr4-38773268-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030956.4(TLR10):​c.2323A>G​(p.Ile775Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,611,796 control chromosomes in the GnomAD database, including 23,983 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I775F) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.14 (1872 hom., cov: 32)
  • Exomes 𝑓: 0.16 (22111 hom.)
• Consequence: TLR10 NM_030956.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.339

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=0.005084753).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.264 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TLR10	NM_030956.4	c.2323A>G	p.Ile775Val	missense_variant	4/4	ENST00000308973.9	NP_112218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TLR10	ENST00000308973.9	c.2323A>G	p.Ile775Val	missense_variant	4/4	5	NM_030956.4	ENSP00000308925.4

Frequencies

GnomAD3 genomes AF: 0.135 AC: 20588 AN: 152064 Hom.: 1872 Cov.: 32

Gnomad AFR AF: 0.0317

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.276

Gnomad EAS AF: 0.275

Gnomad SAS AF: 0.175

Gnomad FIN AF: 0.0781

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.188

GnomAD3 exomes AF: 0.168 AC: 41690 AN: 248768 Hom.: 4219 AF XY: 0.175 AC XY: 23588 AN XY: 134512

Gnomad AFR exome AF: 0.0265

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.262

Gnomad EAS exome AF: 0.265

Gnomad SAS exome AF: 0.189

Gnomad FIN exome AF: 0.0812

Gnomad NFE exome AF: 0.190

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.164 AC: 239772 AN: 1459614 Hom.: 22111 Cov.: 35 AF XY: 0.167 AC XY: 121121 AN XY: 726070

Gnomad4 AFR exome AF: 0.0285

Gnomad4 AMR exome AF: 0.120

Gnomad4 ASJ exome AF: 0.266

Gnomad4 EAS exome AF: 0.346

Gnomad4 SAS exome AF: 0.189

Gnomad4 FIN exome AF: 0.0837

Gnomad4 NFE exome AF: 0.163

Gnomad4 OTH exome AF: 0.158

GnomAD4 genome AF: 0.135 AC: 20580 AN: 152182 Hom.: 1872 Cov.: 32 AF XY: 0.132 AC XY: 9856 AN XY: 74416

Gnomad4 AFR AF: 0.0316

Gnomad4 AMR AF: 0.168

Gnomad4 ASJ AF: 0.276

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.177

Gnomad4 FIN AF: 0.0781

Gnomad4 NFE AF: 0.175

Gnomad4 OTH AF: 0.185

Alfa AF: 0.187 Hom.: 6544

Bravo AF: 0.141

TwinsUK AF: 0.171 AC: 633

ALSPAC AF: 0.188 AC: 726

ESP6500AA AF: 0.0293 AC: 129

ESP6500EA AF: 0.173 AC: 1492

ExAC AF: 0.174 AC: 21106

Asia WGS AF: 0.164 AC: 571 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.79	T
BayesDel_noAF	Benign	-0.76
CADD	Benign	0.14
DANN	Benign	0.28
DEOGEN2	Benign	0.027	T;T;T;T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.63	.;.;.;T;.;.
MetaRNN	Benign	0.0051	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.3	L;L;L;L;L;L
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.73	N;.;N;.;N;N
REVEL	Benign	0.043
Sift	Benign	0.23	T;.;T;.;T;T
Sift4G	Benign	0.22	T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;B
Vest4		0.029
MPC		0.047
ClinPred		0.00030	T
GERP RS		-5.3
Varity_R		0.12
gMVP		0.062

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: rs4129009; hg19: chr4-38774889; COSMIC: COSV58301605; COSMIC: COSV58301605;