17-3566832-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_080704.4(TRPV1):c.2503G>A(p.Ala835Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000123 in 1,461,560 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.305

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13715264).
• BS2: High AC in GnomAdExome at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV1	NM_080704.4	c.2503G>A	p.Ala835Thr	missense_variant	17/17	ENST00000572705.2
TRPV1	NM_018727.5	c.2503G>A	p.Ala835Thr	missense_variant	16/16
TRPV1	NM_080705.4	c.2503G>A	p.Ala835Thr	missense_variant	16/16
TRPV1	NM_080706.3	c.2503G>A	p.Ala835Thr	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV1	ENST00000572705.2	c.2503G>A	p.Ala835Thr	missense_variant	17/17	1	NM_080704.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.0000442 AC: 11 AN: 249092 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000203

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000223

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1461560 Hom.: 0 Cov.: 30 AF XY: 0.0000110 AC XY: 8 AN XY: 727064

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000179

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 31

ExAC AF: 0.0000414 AC: 5

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 26, 2022

The c.2503G>A (p.A835T) alteration is located in exon 15 (coding exon 15) of the TRPV1 gene. This alteration results from a G to A substitution at nucleotide position 2503, causing the alanine (A) at amino acid position 835 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	7.8
Dann	Uncertain	0.99
DEOGEN2	Benign	0.27	T;T;T;T;.;.;.
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.9	M;M;M;M;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.81	N;.;.;N;N;.;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.0080	D;.;.;D;D;.;D
Sift4G	Uncertain	0.016	D;D;D;D;D;D;D
Polyphen		0.57	P;P;P;P;B;.;P
Vest4		0.045
MutPred		0.086		.;.;.;.;Gain of phosphorylation at A846 (P = 0.0244);.;.;
MVP		0.69
MPC		0.062
ClinPred		0.098	T
GERP RS		4.8
Varity_R		0.068
gMVP		0.33

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: rs200108152; hg19: chr17-3470126; COSMIC: COSV51518890;