17-3577170-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.1736G>A(p.Arg579His) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,585,634 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: TRPV1 NM_080704.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.37

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=0.22049475).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPV1	NM_080704.4	c.1736G>A	p.Arg579His	missense_variant	13/17	ENST00000572705.2
TRPV1	NM_018727.5	c.1736G>A	p.Arg579His	missense_variant	12/16
TRPV1	NM_080705.4	c.1736G>A	p.Arg579His	missense_variant	12/16
TRPV1	NM_080706.3	c.1736G>A	p.Arg579His	missense_variant	11/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPV1	ENST00000572705.2	c.1736G>A	p.Arg579His	missense_variant	13/17	1	NM_080704.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000490 AC: 10 AN: 204086 Hom.: 0 AF XY: 0.0000456 AC XY: 5 AN XY: 109574

Gnomad AFR exome AF: 0.000170

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000690

Gnomad SAS exome AF: 0.000159

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000334

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000363 AC: 52 AN: 1433286 Hom.: 1 Cov.: 32 AF XY: 0.0000296 AC XY: 21 AN XY: 710118

Gnomad4 AFR exome AF: 0.0000305

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000981

Gnomad4 FIN exome AF: 0.0000389

Gnomad4 NFE exome AF: 0.0000355

Gnomad4 OTH exome AF: 0.0000168

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74498

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000302

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000247 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000500 AC: 6

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

Mar 07, 2024

The c.1736G>A (p.R579H) alteration is located in exon 11 (coding exon 11) of the TRPV1 gene. This alteration results from a G to A substitution at nucleotide position 1736, causing the arginine (R) at amino acid position 579 to be replaced by a histidine (H). 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	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D;D;D;.;.;.
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.22	T;T;T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.7	M;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-4.0	D;.;.;D;D;.;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.026	D;.;.;D;D;.;D
Sift4G	Uncertain	0.057	T;T;T;T;T;T;T
Polyphen		0.86	P;P;P;P;D;.;D
Vest4		0.34
MVP		0.78
MPC		0.41
ClinPred		0.81	D
GERP RS		5.2
Varity_R		0.38
gMVP		0.85

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: rs375321968; hg19: chr17-3480464;