rs199473704

Variant names:

• chr17-3524224-C-A
• rs199473704
• NM_145068.4:c.1717G>T

Your query was ambiguous. Multiple possible variants found:

• chr17-3524224-C-A
• chr17-3524224-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The ENST00000576742.6(TRPV3):​c.1717G>T​(p.Gly573Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G573V) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPV3 ENST00000576742.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:2 O:1
• Conservation: PhyloP100: 7.47
• Publications: 68 publications found

Genes affected

TRPV3 (HGNC:18084): (transient receptor potential cation channel subfamily V member 3) This gene product belongs to a family of nonselective cation channels that function in a variety of processes, including temperature sensation and vasoregulation. The thermosensitive members of this family are expressed in subsets of sensory neurons that terminate in the skin, and are activated at distinct physiological temperatures. This channel is activated at temperatures between 22 and 40 degrees C. This gene lies in close proximity to another family member gene on chromosome 17, and the two encoded proteins are thought to associate with each other to form heteromeric channels. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2012]

TRPV3 Gene-Disease associations (from GenCC):

• mutilating palmoplantar keratoderma with periorificial keratotic plaques

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Ambry Genetics, Orphanet
• Olmsted syndrome 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• isolated focal non-epidermolytic palmoplantar keratoderma

  Inheritance: Unknown, AD Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000576742.6
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-3524223-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 391510.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant 17-3524224-C-A is Pathogenic according to our data. Variant chr17-3524224-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 30637.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000576742.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV3	NM_145068.4	MANE Select	c.1717G>T	p.Gly573Cys	missense	Exon 13 of 18	NP_659505.1
	TRPV3	NM_001258205.2		c.1717G>T	p.Gly573Cys	missense	Exon 13 of 18	NP_001245134.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV3	ENST00000576742.6	TSL:1 MANE Select	c.1717G>T	p.Gly573Cys	missense	Exon 13 of 18	ENSP00000461518.2
	TRPV3	ENST00000301365.8	TSL:1	c.1717G>T	p.Gly573Cys	missense	Exon 13 of 18	ENSP00000301365.4
	TRPV3	ENST00000572519.1	TSL:1	c.1717G>T	p.Gly573Cys	missense	Exon 13 of 17	ENSP00000460215.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (2)
1	-	-	Olmsted syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.93	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.48	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.5
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-8.4	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.99	D
Vest4		0.98
MutPred		0.87		Gain of helix (P = 0.0199)
MVP		0.85
MPC		0.71
ClinPred		1.0	D
GERP RS		4.8
Varity_R		0.94
gMVP		0.93
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs199473704; hg19: chr17-3427518;