GeneBe

12-109794371-G-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_021625.5(TRPV4):​c.1449C>A​(p.Val483Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,238 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. Synonymous variant affecting the same amino acid position (i.e. V483V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TRPV4
NM_021625.5 synonymous

Scores

2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.21

Publications

0 publications found
Variant links:
Genes affected
TRPV4 (HGNC:18083): (transient receptor potential cation channel subfamily V member 4) This gene encodes a member of the OSM9-like transient receptor potential channel (OTRPC) subfamily in the transient receptor potential (TRP) superfamily of ion channels. The encoded protein is a Ca2+-permeable, nonselective cation channel that is thought to be involved in the regulation of systemic osmotic pressure. Mutations in this gene are the cause of spondylometaphyseal and metatropic dysplasia and hereditary motor and sensory neuropathy type IIC. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2010]
TRPV4 Gene-Disease associations (from GenCC):
  • metatropic dysplasia
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
  • neuromuscular disease
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • spondylometaphyseal dysplasia, Kozlowski type
    Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet
  • TRPV4-related bone disorder
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen, Illumina
  • autosomal dominant brachyolmia
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
  • Charcot-Marie-Tooth disease axonal type 2C
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
  • scapuloperoneal spinal muscular atrophy, autosomal dominant
    Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
  • familial avascular necrosis of femoral head
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • familial digital arthropathy-brachydactyly
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • neuronopathy, distal hereditary motor, autosomal dominant 8
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • parastremmatic dwarfism
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TRPV4NM_021625.5 linkc.1449C>A p.Val483Val synonymous_variant Exon 8 of 16 ENST00000261740.7 NP_067638.3 Q9HBA0-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TRPV4ENST00000261740.7 linkc.1449C>A p.Val483Val synonymous_variant Exon 8 of 16 1 NM_021625.5 ENSP00000261740.2 Q9HBA0-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461238
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726968
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:
0
AN:
33480
American (AMR)
AF:
0.00
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26136
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.0000116
AC:
1
AN:
86248
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52786
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5768
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1112008
Other (OTH)
AF:
0.00
AC:
0
AN:
60388
⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.275
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.49
CADD
Benign
19
DANN
Benign
0.81
PhyloP100
2.2

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.67
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.67
Position offset: 3

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

Publications

Other links and lift over

dbSNP: rs1060504550; hg19: chr12-110232176; API