17-3583408-G-A

Variant names:

• chr17-3583408-G-A
• rs224534
• NM_080704.4:c.1406C>T

Variant summary

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

The NM_080704.4(TRPV1):​c.1406C>T​(p.Thr469Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.36 in 1,603,258 control chromosomes in the GnomAD database, including 112,346 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.31 (9156 hom., cov: 33)
  • Exomes 𝑓: 0.37 (103190 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27

Genes affected

TRPV1 (HGNC:12716): (transient receptor potential cation channel subfamily V member 1) Capsaicin, the main pungent ingredient in hot chili peppers, elicits a sensation of burning pain by selectively activating sensory neurons that convey information about noxious stimuli to the central nervous system. The protein encoded by this gene is a receptor for capsaicin and is a non-selective cation channel that is structurally related to members of the TRP family of ion channels. This receptor is also activated by increases in temperature in the noxious range, suggesting that it functions as a transducer of painful thermal stimuli in vivo. Four transcript variants encoding the same protein, but with different 5' UTR sequence, have been described for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=2.0098341E-6).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV1	NM_080704.4	c.1406C>T	p.Thr469Ile	missense_variant	Exon 10 of 17	ENST00000572705.2	NP_542435.2
TRPV1	NM_018727.5	c.1406C>T	p.Thr469Ile	missense_variant	Exon 9 of 16		NP_061197.4
TRPV1	NM_080705.4	c.1406C>T	p.Thr469Ile	missense_variant	Exon 9 of 16		NP_542436.2
TRPV1	NM_080706.3	c.1406C>T	p.Thr469Ile	missense_variant	Exon 8 of 15		NP_542437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV1	ENST00000572705.2	c.1406C>T	p.Thr469Ile	missense_variant	Exon 10 of 17	1	NM_080704.4	ENSP00000459962.1

Frequencies

GnomAD3 genomes AF: 0.306 AC: 46534 AN: 152086 Hom.: 9151 Cov.: 33

Gnomad AFR AF: 0.0805

Gnomad AMI AF: 0.277

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.384

Gnomad EAS AF: 0.770

Gnomad SAS AF: 0.434

Gnomad FIN AF: 0.464

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.357

Gnomad OTH AF: 0.318

GnomAD2 exomes AF: 0.394 AC: 92858 AN: 235758 AF XY: 0.395

Gnomad AFR exome AF: 0.0709

Gnomad AMR exome AF: 0.399

Gnomad ASJ exome AF: 0.385

Gnomad EAS exome AF: 0.771

Gnomad FIN exome AF: 0.454

Gnomad NFE exome AF: 0.357

Gnomad OTH exome AF: 0.371

GnomAD4 exome AF: 0.366 AC: 530538 AN: 1451054 Hom.: 103190 Cov.: 34 AF XY: 0.368 AC XY: 265019 AN XY: 720904

Gnomad4 AFR exome AF: 0.0662 AC: 2211 AN: 33374

Gnomad4 AMR exome AF: 0.392 AC: 16950 AN: 43280

Gnomad4 ASJ exome AF: 0.386 AC: 9972 AN: 25826

Gnomad4 EAS exome AF: 0.753 AC: 29739 AN: 39488

Gnomad4 SAS exome AF: 0.418 AC: 35271 AN: 84362

Gnomad4 FIN exome AF: 0.450 AC: 23820 AN: 52912

Gnomad4 NFE exome AF: 0.351 AC: 388657 AN: 1106022

Gnomad4 Remaining exome AF: 0.365 AC: 21920 AN: 60038

GnomAD4 genome AF: 0.306 AC: 46546 AN: 152204 Hom.: 9156 Cov.: 33 AF XY: 0.316 AC XY: 23543 AN XY: 74412

Gnomad4 AFR AF: 0.0804 AC: 0.0803503 AN: 0.0803503

Gnomad4 AMR AF: 0.369 AC: 0.368848 AN: 0.368848

Gnomad4 ASJ AF: 0.384 AC: 0.383573 AN: 0.383573

Gnomad4 EAS AF: 0.771 AC: 0.770568 AN: 0.770568

Gnomad4 SAS AF: 0.433 AC: 0.432891 AN: 0.432891

Gnomad4 FIN AF: 0.464 AC: 0.463887 AN: 0.463887

Gnomad4 NFE AF: 0.356 AC: 0.356426 AN: 0.356426

Gnomad4 OTH AF: 0.325 AC: 0.324811 AN: 0.324811

Alfa AF: 0.342 Hom.: 38263

Bravo AF: 0.291

TwinsUK AF: 0.362 AC: 1343

ALSPAC AF: 0.347 AC: 1336

ESP6500AA AF: 0.0852 AC: 325

ESP6500EA AF: 0.344 AC: 2842

ExAC AF: 0.377 AC: 45465

Asia WGS AF: 0.608 AC: 2114 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Uncertain	-0.040
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;D;D;D;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.44	.;.;.;T;T;T;T
MetaRNN	Benign	0.0000020	T;T;T;T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.9	M;M;M;M;.;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-3.3	D;.;.;D;D;.;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.019	D;.;.;D;D;.;D
Sift4G	Uncertain	0.012	D;D;D;D;D;D;D
Polyphen		0.025	B;B;B;B;B;.;B
Vest4		0.15
MPC		0.074
ClinPred		0.017	T
GERP RS		4.1
Varity_R		0.094
gMVP		0.23
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
SpliceAI score (max)		0.010		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: rs224534; hg19: chr17-3486702; COSMIC: COSV51516848; COSMIC: COSV51516848;