chr4-38774018-G-A

Variant names:

• chr4-38774018-G-A
• rs11466658
• NM_030956.4:c.1573C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_030956.4(TLR10):​c.1573C>T​(p.Arg525Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0269 in 1,606,620 control chromosomes in the GnomAD database, including 706 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R525Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.025 (63 hom., cov: 32)
  • Exomes 𝑓: 0.027 (643 hom.)
• Consequence: TLR10 NM_030956.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.257
• Publications: 24 publications found

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0037816763).
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0253 (3852/152228) while in subpopulation SAS AF = 0.0437 (211/4826). AF 95% confidence interval is 0.0389. There are 63 homozygotes in GnomAd4. There are 1849 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 63 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TLR10	NM_030956.4	c.1573C>T	p.Arg525Trp	missense_variant	Exon 4 of 4	ENST00000308973.9	NP_112218.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TLR10	ENST00000308973.9	c.1573C>T	p.Arg525Trp	missense_variant	Exon 4 of 4	5	NM_030956.4	ENSP00000308925.4

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3842 AN: 152110 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0247

Gnomad ASJ AF: 0.0300

Gnomad EAS AF: 0.0113

Gnomad SAS AF: 0.0437

Gnomad FIN AF: 0.0142

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0360

GnomAD2 exomes AF: 0.0271 AC: 6663 AN: 246100 AF XY: 0.0287

Gnomad AFR exome AF: 0.0244

Gnomad AMR exome AF: 0.0152

Gnomad ASJ exome AF: 0.0355

Gnomad EAS exome AF: 0.00895

Gnomad FIN exome AF: 0.0156

Gnomad NFE exome AF: 0.0320

Gnomad OTH exome AF: 0.0247

GnomAD4 exome AF: 0.0270 AC: 39296 AN: 1454392 Hom.: 643 Cov.: 35 AF XY: 0.0276 AC XY: 19933 AN XY: 722780

African (AFR) AF: 0.0239 AC: 793 AN: 33178

American (AMR) AF: 0.0158 AC: 689 AN: 43556

Ashkenazi Jewish (ASJ) AF: 0.0336 AC: 870 AN: 25858

East Asian (EAS) AF: 0.00384 AC: 152 AN: 39568

South Asian (SAS) AF: 0.0392 AC: 3335 AN: 85144

European-Finnish (FIN) AF: 0.0161 AC: 857 AN: 53280

Middle Eastern (MID) AF: 0.0330 AC: 189 AN: 5732

European-Non Finnish (NFE) AF: 0.0278 AC: 30818 AN: 1108024

Other (OTH) AF: 0.0265 AC: 1593 AN: 60052

GnomAD4 genome AF: 0.0253 AC: 3852 AN: 152228 Hom.: 63 Cov.: 32 AF XY: 0.0248 AC XY: 1849 AN XY: 74430

African (AFR) AF: 0.0234 AC: 973 AN: 41526

American (AMR) AF: 0.0247 AC: 377 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0300 AC: 104 AN: 3472

East Asian (EAS) AF: 0.0114 AC: 59 AN: 5190

South Asian (SAS) AF: 0.0437 AC: 211 AN: 4826

European-Finnish (FIN) AF: 0.0142 AC: 150 AN: 10598

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0275 AC: 1872 AN: 68024

Other (OTH) AF: 0.0399 AC: 84 AN: 2106

Alfa AF: 0.0274 Hom.: 198

Bravo AF: 0.0255

TwinsUK AF: 0.0280 AC: 104

ALSPAC AF: 0.0280 AC: 108

ESP6500AA AF: 0.0243 AC: 107

ESP6500EA AF: 0.0313 AC: 269

ExAC AF: 0.0291 AC: 3535

Asia WGS AF: 0.0450 AC: 159 AN: 3478

EpiCase AF: 0.0277

EpiControl AF: 0.0289

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	11
DANN	Benign	0.80
DEOGEN2	Benign	0.27	T;T;T;T;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.80	.;.;.;T;.;.
MetaRNN	Benign	0.0038	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L;L;L;L;L;L
PhyloP100		-0.26
PrimateAI	Benign	0.18	T
PROVEAN	Uncertain	-3.7	D;.;D;.;D;D
REVEL	Benign	0.034
Sift	Uncertain	0.027	D;.;D;.;D;D
Sift4G	Uncertain	0.0060	D;D;D;D;D;D
Polyphen		0.0040	B;B;B;B;B;B
Vest4		0.077
MPC		0.055
ClinPred		0.0080	T
GERP RS		-1.7
Varity_R		0.099
gMVP		0.25
Mutation Taster		=100/0	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: rs11466658; hg19: chr4-38775639;