4-38774486-T-G

Variant names:

• chr4-38774486-T-G
• rs11096955
• NM_030956.4:c.1105A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_030956.4(TLR10):​c.1105A>C​(p.Ile369Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 1,596,826 control chromosomes in the GnomAD database, including 109,548 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 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. I369T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.42 (13913 hom., cov: 32)
  • Exomes 𝑓: 0.35 (95635 hom.)
• Consequence: TLR10 NM_030956.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.577
• Publications: 79 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=7.11327E-5).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030956.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR10	NM_030956.4	MANE Select	c.1105A>C	p.Ile369Leu	missense	Exon 4 of 4	NP_112218.2	Q9BXR5
	TLR10	NM_001017388.3		c.1105A>C	p.Ile369Leu	missense	Exon 2 of 2	NP_001017388.1	Q9BXR5
	TLR10	NM_001195106.2		c.1105A>C	p.Ile369Leu	missense	Exon 3 of 3	NP_001182035.1	Q9BXR5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TLR10	ENST00000308973.9	TSL:5 MANE Select	c.1105A>C	p.Ile369Leu	missense	Exon 4 of 4	ENSP00000308925.4	Q9BXR5
	TLR10	ENST00000361424.6	TSL:1	c.1105A>C	p.Ile369Leu	missense	Exon 2 of 2	ENSP00000354459.2	Q9BXR5
	TLR10	ENST00000506111.1	TSL:1	c.1105A>C	p.Ile369Leu	missense	Exon 2 of 2	ENSP00000421483.1	Q9BXR5

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63424 AN: 151922 Hom.: 13875 Cov.: 32

Gnomad AFR AF: 0.516

Gnomad AMI AF: 0.391

Gnomad AMR AF: 0.411

Gnomad ASJ AF: 0.502

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.545

Gnomad FIN AF: 0.345

Gnomad MID AF: 0.590

Gnomad NFE AF: 0.346

Gnomad OTH AF: 0.473

GnomAD2 exomes AF: 0.415 AC: 97281 AN: 234678 AF XY: 0.423

Gnomad AFR exome AF: 0.517

Gnomad AMR exome AF: 0.343

Gnomad ASJ exome AF: 0.495

Gnomad EAS exome AF: 0.533

Gnomad FIN exome AF: 0.349

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.419

GnomAD4 exome AF: 0.351 AC: 507525 AN: 1444786 Hom.: 95635 Cov.: 37 AF XY: 0.360 AC XY: 258378 AN XY: 717960

African (AFR) AF: 0.527 AC: 17066 AN: 32368

American (AMR) AF: 0.351 AC: 14063 AN: 40034

Ashkenazi Jewish (ASJ) AF: 0.496 AC: 12542 AN: 25288

East Asian (EAS) AF: 0.573 AC: 22680 AN: 39572

South Asian (SAS) AF: 0.560 AC: 46251 AN: 82518

European-Finnish (FIN) AF: 0.344 AC: 18234 AN: 53056

Middle Eastern (MID) AF: 0.600 AC: 3398 AN: 5662

European-Non Finnish (NFE) AF: 0.317 AC: 350672 AN: 1106604

Other (OTH) AF: 0.379 AC: 22619 AN: 59684

GnomAD4 genome AF: 0.418 AC: 63499 AN: 152040 Hom.: 13913 Cov.: 32 AF XY: 0.418 AC XY: 31079 AN XY: 74330

African (AFR) AF: 0.516 AC: 21403 AN: 41452

American (AMR) AF: 0.411 AC: 6282 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.502 AC: 1742 AN: 3468

East Asian (EAS) AF: 0.534 AC: 2769 AN: 5182

South Asian (SAS) AF: 0.547 AC: 2639 AN: 4826

European-Finnish (FIN) AF: 0.345 AC: 3649 AN: 10578

Middle Eastern (MID) AF: 0.593 AC: 172 AN: 290

European-Non Finnish (NFE) AF: 0.346 AC: 23489 AN: 67954

Other (OTH) AF: 0.473 AC: 998 AN: 2108

Alfa AF: 0.391 Hom.: 24545

Bravo AF: 0.423

TwinsUK AF: 0.316 AC: 1171

ALSPAC AF: 0.335 AC: 1293

ESP6500AA AF: 0.507 AC: 2232

ESP6500EA AF: 0.343 AC: 2951

ExAC AF: 0.428 AC: 51975

Asia WGS AF: 0.514 AC: 1789 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.7
DANN	Benign	0.86
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.000071	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.58
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.035
Sift	Benign	0.33	T
Sift4G	Benign	0.31	T
Polyphen		0.0	B
Vest4		0.051
MPC		0.053
ClinPred		0.0022	T
GERP RS		1.2
Varity_R		0.066
gMVP		0.51
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: rs11096955; hg19: chr4-38776107; COSMIC: COSV58300511; COSMIC: COSV58300511;