rs929739314

Variant names:

• chr12-109783121-G-A
• rs929739314
• NM_021625.5:c.*500C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_021625.5(TRPV4):​c.*500C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00021 in 152,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TRPV4 NM_021625.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:6
• Conservation: PhyloP100: -0.302
• Publications: 0 publications found

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: G2P, ClinGen, Orphanet
• neuromuscular disease

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• spondylometaphyseal dysplasia, Kozlowski type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen
• TRPV4-related bone disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: Illumina, ClinGen
• autosomal dominant brachyolmia

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• Charcot-Marie-Tooth disease axonal type 2C

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• brachyolmia

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• scapuloperoneal spinal muscular atrophy, autosomal dominant

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics
• spondyloepimetaphyseal dysplasia, Maroteaux type

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• 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

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00021 (32/152282) while in subpopulation AFR AF = 0.00065 (27/41550). AF 95% confidence interval is 0.000459. There are 0 homozygotes in GnomAd4. There are 12 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 32 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021625.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	NM_021625.5	MANE Select	c.*500C>T		3_prime_UTR	Exon 16 of 16	NP_067638.3
	TRPV4	NM_001177431.1		c.*500C>T		3_prime_UTR	Exon 16 of 16	NP_001170902.1	Q9HBA0-5
	TRPV4	NM_001177428.1		c.*500C>T		3_prime_UTR	Exon 14 of 14	NP_001170899.1	Q9HBA0-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPV4	ENST00000261740.7	TSL:1 MANE Select	c.*500C>T		3_prime_UTR	Exon 16 of 16	ENSP00000261740.2	Q9HBA0-1
	TRPV4	ENST00000418703.7	TSL:1	c.*500C>T		3_prime_UTR	Exon 15 of 15	ENSP00000406191.2	Q9HBA0-1
	TRPV4	ENST00000675670.1		c.*500C>T		3_prime_UTR	Exon 16 of 16	ENSP00000502135.1	Q9HBA0-1

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000652

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 3324 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 1712

African (AFR) AF: 0.00 AC: 0 AN: 58

American (AMR) AF: 0.00 AC: 0 AN: 260

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 68

East Asian (EAS) AF: 0.00 AC: 0 AN: 38

South Asian (SAS) AF: 0.00 AC: 0 AN: 170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 304

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 8

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2238

Other (OTH) AF: 0.00 AC: 0 AN: 180

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74452

African (AFR) AF: 0.000650 AC: 27 AN: 41550

American (AMR) AF: 0.0000654 AC: 1 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.000238

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Brachyrachia (short spine dysplasia) (1)
-	1	-	Charcot-Marie-Tooth disease axonal type 2C (1)
-	1	-	Metatropic dysplasia (1)
-	1	-	Neuronopathy, distal hereditary motor, autosomal dominant 8 (1)
-	1	-	Scapuloperoneal spinal muscular atrophy (1)
-	1	-	Spondylometaphyseal dysplasia, Kozlowski type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.68
DANN	Benign	0.78
PhyloP100		-0.30

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: rs929739314; hg19: chr12-110220926;