17-3580491-T-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_080704.4(TRPV1):c.1513A>G(p.Thr505Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00403 in 1,613,960 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (26 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.427

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

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009269506).
• BP6: Variant 17-3580491-T-C is Benign according to our data. Variant chr17-3580491-T-C is described in ClinVar as [Benign]. Clinvar id is 774344.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 450 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV1	NM_080704.4	c.1513A>G	p.Thr505Ala	missense_variant	11/17	ENST00000572705.2
TRPV1	NM_018727.5	c.1513A>G	p.Thr505Ala	missense_variant	10/16
TRPV1	NM_080705.4	c.1513A>G	p.Thr505Ala	missense_variant	10/16
TRPV1	NM_080706.3	c.1513A>G	p.Thr505Ala	missense_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV1	ENST00000572705.2	c.1513A>G	p.Thr505Ala	missense_variant	11/17	1	NM_080704.4	P1

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152136 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.000660

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00472

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00384 AC: 958 AN: 249262 Hom.: 6 AF XY: 0.00439 AC XY: 593 AN XY: 135226

Gnomad AFR exome AF: 0.000969

Gnomad AMR exome AF: 0.000811

Gnomad ASJ exome AF: 0.00159

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00820

Gnomad FIN exome AF: 0.000650

Gnomad NFE exome AF: 0.00536

Gnomad OTH exome AF: 0.00463

GnomAD4 exome AF: 0.00414 AC: 6055 AN: 1461706 Hom.: 26 Cov.: 31 AF XY: 0.00430 AC XY: 3126 AN XY: 727138

Gnomad4 AFR exome AF: 0.000568

Gnomad4 AMR exome AF: 0.00123

Gnomad4 ASJ exome AF: 0.00153

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00869

Gnomad4 FIN exome AF: 0.00107

Gnomad4 NFE exome AF: 0.00434

Gnomad4 OTH exome AF: 0.00401

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152254 Hom.: 2 Cov.: 32 AF XY: 0.00281 AC XY: 209 AN XY: 74448

Gnomad4 AFR AF: 0.000939

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00539

Gnomad4 FIN AF: 0.000660

Gnomad4 NFE AF: 0.00472

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00411 Hom.: 2

Bravo AF: 0.00303

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00149 AC: 6

ESP6500EA AF: 0.00492 AC: 41

ExAC AF: 0.00469 AC: 567

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00456

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	9.2
Dann	Benign	0.72
DEOGEN2	Uncertain	0.68	D;D;D;D;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.96
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.0099	T
MetaRNN	Benign	0.0093	T;T;T;T;T;T;T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.18	N;N;N;N;.;.;.
MutationTaster	Benign	0.79	N;N;N;N;N;N;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.67	N;.;.;N;N;.;N
REVEL	Uncertain	0.36
Sift	Benign	0.41	T;.;.;T;T;.;T
Sift4G	Benign	0.36	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;.;B
Vest4		0.098
MVP		0.11
MPC		0.063
ClinPred		0.0026	T
GERP RS		-3.2
Varity_R		0.023
gMVP		0.28

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: rs17633288; hg19: chr17-3483785; COSMIC: COSV99063666; COSMIC: COSV99063666;