17-3573901-G-A

Position:

• chr17-3573901-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000572705.2(TRPV1):​c.1835C>T​(p.Thr612Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00127 in 1,610,382 control chromosomes in the GnomAD database, including 4 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 Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T612T) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 30)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: TRPV1 ENST00000572705.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.271

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010294616).
• BP6: Variant 17-3573901-G-A is Benign according to our data. Variant chr17-3573901-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 717635.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 163 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPV1	NM_080704.4	c.1835C>T	p.Thr612Met	missense_variant	14/17	ENST00000572705.2	NP_542435.2
TRPV1	NM_018727.5	c.1835C>T	p.Thr612Met	missense_variant	13/16		NP_061197.4
TRPV1	NM_080705.4	c.1835C>T	p.Thr612Met	missense_variant	13/16		NP_542436.2
TRPV1	NM_080706.3	c.1835C>T	p.Thr612Met	missense_variant	12/15		NP_542437.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPV1	ENST00000572705.2	c.1835C>T	p.Thr612Met	missense_variant	14/17	1	NM_080704.4	ENSP00000459962	P1

Frequencies

GnomAD3 genomes AF: 0.00107 AC: 163 AN: 151920 Hom.: 1 Cov.: 30

Gnomad AFR AF: 0.000411

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00157

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.00124 AC: 302 AN: 244448 Hom.: 1 AF XY: 0.00141 AC XY: 187 AN XY: 133084

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.00141

Gnomad ASJ exome AF: 0.00335

Gnomad EAS exome AF: 0.000113

Gnomad SAS exome AF: 0.000798

Gnomad FIN exome AF: 0.0000935

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00339

GnomAD4 exome AF: 0.00129 AC: 1886 AN: 1458344 Hom.: 3 Cov.: 33 AF XY: 0.00136 AC XY: 990 AN XY: 725592

Gnomad4 AFR exome AF: 0.000333

Gnomad4 AMR exome AF: 0.00135

Gnomad4 ASJ exome AF: 0.00238

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.000850

Gnomad4 FIN exome AF: 0.000414

Gnomad4 NFE exome AF: 0.00143

Gnomad4 OTH exome AF: 0.00111

GnomAD4 genome AF: 0.00107 AC: 163 AN: 152038 Hom.: 1 Cov.: 30 AF XY: 0.000969 AC XY: 72 AN XY: 74322

Gnomad4 AFR AF: 0.000410

Gnomad4 AMR AF: 0.00138

Gnomad4 ASJ AF: 0.00375

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.00157

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.00168 Hom.: 0

Bravo AF: 0.00106

ESP6500AA AF: 0.000522 AC: 2

ESP6500EA AF: 0.00230 AC: 19

ExAC AF: 0.00126 AC: 152

EpiCase AF: 0.00185

EpiControl AF: 0.00243

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 06, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.84
DEOGEN2	Uncertain	0.65	D;D;D;D;.;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.87
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.74	.;.;.;T;T;T;T
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.010	T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.55	N;N;N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-0.90	N;.;.;N;N;.;N
REVEL	Uncertain	0.47
Sift	Benign	0.11	T;.;.;T;T;.;T
Sift4G	Benign	0.098	T;T;T;T;T;T;T
Polyphen		0.010	B;B;B;B;B;.;B
Vest4		0.13
MVP		0.37
MPC		0.068
ClinPred		0.0027	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.60

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs199539626; hg19: chr17-3477195;