17-3589906-C-G

Variant names:

• chr17-3589906-C-G
• rs222747
• NM_080704.4:c.945G>C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_080704.4(TRPV1):​c.945G>C​(p.Met315Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.75 in 1,598,084 control chromosomes in the GnomAD database, including 452,995 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.77 (45571 hom., cov: 32)
  • Exomes 𝑓: 0.75 (407424 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.807

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]

ENSG00000262304 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.156609E-7).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.871 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPV1	NM_080704.4	c.945G>C	p.Met315Ile	missense_variant	Exon 7 of 17	ENST00000572705.2	NP_542435.2
TRPV1	NM_018727.5	c.945G>C	p.Met315Ile	missense_variant	Exon 6 of 16		NP_061197.4
TRPV1	NM_080705.4	c.945G>C	p.Met315Ile	missense_variant	Exon 6 of 16		NP_542436.2
TRPV1	NM_080706.3	c.945G>C	p.Met315Ile	missense_variant	Exon 5 of 15		NP_542437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPV1	ENST00000572705.2	c.945G>C	p.Met315Ile	missense_variant	Exon 7 of 17	1	NM_080704.4	ENSP00000459962.1
ENSG00000262304	ENST00000572919.1	n.*2229G>C		non_coding_transcript_exon_variant	Exon 12 of 14	5		ENSP00000461416.1
ENSG00000262304	ENST00000572919.1	n.*2229G>C		3_prime_UTR_variant	Exon 12 of 14	5		ENSP00000461416.1

Frequencies

GnomAD3 genomes AF: 0.768 AC: 116758 AN: 152004 Hom.: 45546 Cov.: 32

Gnomad AFR AF: 0.879

Gnomad AMI AF: 0.816

Gnomad AMR AF: 0.740

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.433

Gnomad SAS AF: 0.752

Gnomad FIN AF: 0.645

Gnomad MID AF: 0.832

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.767

GnomAD3 exomes AF: 0.723 AC: 159239 AN: 220190 Hom.: 58341 AF XY: 0.725 AC XY: 86586 AN XY: 119470

Gnomad AFR exome AF: 0.880

Gnomad AMR exome AF: 0.733

Gnomad ASJ exome AF: 0.735

Gnomad EAS exome AF: 0.427

Gnomad SAS exome AF: 0.760

Gnomad FIN exome AF: 0.659

Gnomad NFE exome AF: 0.748

Gnomad OTH exome AF: 0.732

GnomAD4 exome AF: 0.748 AC: 1081985 AN: 1445960 Hom.: 407424 Cov.: 83 AF XY: 0.748 AC XY: 536803 AN XY: 717920

Gnomad4 AFR exome AF: 0.890

Gnomad4 AMR exome AF: 0.737

Gnomad4 ASJ exome AF: 0.734

Gnomad4 EAS exome AF: 0.480

Gnomad4 SAS exome AF: 0.760

Gnomad4 FIN exome AF: 0.661

Gnomad4 NFE exome AF: 0.758

Gnomad4 OTH exome AF: 0.744

GnomAD4 genome AF: 0.768 AC: 116832 AN: 152124 Hom.: 45571 Cov.: 32 AF XY: 0.760 AC XY: 56497 AN XY: 74350

Gnomad4 AFR AF: 0.879

Gnomad4 AMR AF: 0.740

Gnomad4 ASJ AF: 0.738

Gnomad4 EAS AF: 0.434

Gnomad4 SAS AF: 0.754

Gnomad4 FIN AF: 0.645

Gnomad4 NFE AF: 0.753

Gnomad4 OTH AF: 0.763

Alfa AF: 0.746 Hom.: 32124

Bravo AF: 0.775

TwinsUK AF: 0.751 AC: 2783

ALSPAC AF: 0.758 AC: 2923

ESP6500AA AF: 0.884 AC: 3764

ESP6500EA AF: 0.762 AC: 6471

ExAC AF: 0.712 AC: 85744

Asia WGS AF: 0.631 AC: 2197 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.58
DEOGEN2	Benign	0.24	T;T;T;T;.;.;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.027	.;.;.;T;T;T;T
MetaRNN	Benign	6.2e-7	T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.6	N;N;N;N;.;.;.
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	1.1	N;.;.;N;N;.;N
REVEL	Benign	0.066
Sift	Benign	1.0	T;.;.;T;T;.;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T
Polyphen		0.0	B;B;B;B;B;.;B
Vest4		0.10
MutPred		0.41		Gain of catalytic residue at M315 (P = 0.0678);Gain of catalytic residue at M315 (P = 0.0678);Gain of catalytic residue at M315 (P = 0.0678);Gain of catalytic residue at M315 (P = 0.0678);Gain of catalytic residue at M315 (P = 0.0678);Gain of catalytic residue at M315 (P = 0.0678);Gain of catalytic residue at M315 (P = 0.0678);
MPC		0.070
ClinPred		0.0015	T
GERP RS		2.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.29

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: rs222747; hg19: chr17-3493200; COSMIC: COSV51514986;