17-3577139-G-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.1767C>G(p.Phe589Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,586,946 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00094 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (3 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.650

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=0.01849866).
• BP6: Variant 17-3577139-G-C is Benign according to our data. Variant chr17-3577139-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 773586.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 143 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV1	NM_080704.4	c.1767C>G	p.Phe589Leu	missense_variant	13/17	ENST00000572705.2
TRPV1	NM_018727.5	c.1767C>G	p.Phe589Leu	missense_variant	12/16
TRPV1	NM_080705.4	c.1767C>G	p.Phe589Leu	missense_variant	12/16
TRPV1	NM_080706.3	c.1767C>G	p.Phe589Leu	missense_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV1	ENST00000572705.2	c.1767C>G	p.Phe589Leu	missense_variant	13/17	1	NM_080704.4	P1

Frequencies

GnomAD3 genomes AF: 0.000940 AC: 143 AN: 152124 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.000754

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00137

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000927 AC: 193 AN: 208094 Hom.: 1 AF XY: 0.000850 AC XY: 95 AN XY: 111746

Gnomad AFR exome AF: 0.000414

Gnomad AMR exome AF: 0.000981

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000704

Gnomad FIN exome AF: 0.000312

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.000557

GnomAD4 exome AF: 0.00162 AC: 2320 AN: 1434704 Hom.: 3 Cov.: 33 AF XY: 0.00154 AC XY: 1093 AN XY: 710978

Gnomad4 AFR exome AF: 0.000244

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.0000391

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000978

Gnomad4 FIN exome AF: 0.000310

Gnomad4 NFE exome AF: 0.00191

Gnomad4 OTH exome AF: 0.00129

GnomAD4 genome AF: 0.000939 AC: 143 AN: 152242 Hom.: 1 Cov.: 32 AF XY: 0.000941 AC XY: 70 AN XY: 74424

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.000754

Gnomad4 NFE AF: 0.00137

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.0000641 Hom.: 0

Bravo AF: 0.000963

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00144 AC: 12

ExAC AF: 0.000865 AC: 104

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 19, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	1.1
Dann	Benign	0.87
DEOGEN2	Uncertain	0.70	D;D;D;D;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.018	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	N;N;N;N;.;.;.
MutationTaster	Benign	0.97	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.6	N;.;.;N;N;.;N
REVEL	Uncertain	0.40
Sift	Benign	0.54	T;.;.;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.011	B;B;B;B;B;.;B
Vest4		0.25
MutPred		0.47		.;.;.;.;Loss of catalytic residue at G601 (P = 0.1562);.;.;
MVP		0.21
MPC		0.074
ClinPred		0.013	T
GERP RS		-4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs9913209; hg19: chr17-3480433; COSMIC: COSV51517458; COSMIC: COSV51517458;