Genetic Variant NM_080704.4:c.1873G>T (chr17-3573863-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_080704.4(TRPV1):c.1873G>T(p.Asp625Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,389,066 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D625N) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

TRPV1
NM_080704.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.397

Publications

0 publications found

Variant links:

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]

TRPV1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2181516).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_080704.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPV1	NM_080704.4	MANE Select	c.1873G>T	p.Asp625Tyr	missense	Exon 14 of 17	NP_542435.2	Q8NER1-1
TRPV1	NM_018727.5		c.1873G>T	p.Asp625Tyr	missense	Exon 13 of 16	NP_061197.4	Q8NER1-1
TRPV1	NM_080705.4		c.1873G>T	p.Asp625Tyr	missense	Exon 13 of 16	NP_542436.2	Q8NER1-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TRPV1	ENST00000572705.2	TSL:1 MANE Select	c.1873G>T	p.Asp625Tyr	missense	Exon 14 of 17	ENSP00000459962.1	Q8NER1-1
TRPV1	ENST00000425167.6	TSL:1	c.1906G>T	p.Asp636Tyr	missense	Exon 13 of 16	ENSP00000409627.2	E7EQ78
TRPV1	ENST00000399756.8	TSL:1	c.1873G>T	p.Asp625Tyr	missense	Exon 12 of 15	ENSP00000382659.4	Q8NER1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.20e-7

AC:

AN:

1389066

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

692404

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30818

American (AMR)

AF:

0.00

AC:

AN:

42438

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22518

East Asian (EAS)

AF:

0.00

AC:

AN:

34086

South Asian (SAS)

AF:

0.00

AC:

AN:

85470

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46084

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4166

European-Non Finnish (NFE)

AF:

9.36e-7

AC:

AN:

1068642

Other (OTH)

AF:

0.00

AC:

AN:

54844

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Uncertain

-0.010

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.70

Eigen

Benign

-0.77

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.83

M_CAP

Uncertain

0.21

MetaRNN

Benign

0.22

MetaSVM

Uncertain

-0.24

MutationAssessor

Benign

0.0

PhyloP100

-0.40

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.6

REVEL

Uncertain

0.60

Sift

Uncertain

0.016

Sift4G

Uncertain

0.012

Polyphen

0.029

Vest4

0.43

MutPred

0.36

Gain of catalytic residue at D636 (P = 0.0184)

MVP

0.54

MPC

0.13

ClinPred

0.18

GERP RS

-0.66

Varity_R

0.11

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over