rs149541389

Variant names:

• chr12-109796714-G-A
• rs149541389
• NM_021625.5:c.1153-10C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_021625.5(TRPV4):​c.1153-10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00739 in 1,605,754 control chromosomes in the GnomAD database, including 53 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (49 hom.)
• Consequence: TRPV4 NM_021625.5 intron
• Scores: Splicing: ADA: 0.00002116
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -1.36
• 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: Orphanet, G2P, ClinGen
• neuromuscular disease

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, 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), Genomics England PanelApp, Orphanet
• Charcot-Marie-Tooth disease axonal type 2C

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

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

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 12-109796714-G-A is Benign according to our data. Variant chr12-109796714-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 137724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00553 (843/152310) while in subpopulation NFE AF = 0.00885 (602/68020). AF 95% confidence interval is 0.00827. There are 4 homozygotes in GnomAd4. There are 406 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 843 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.1153-10C>T		intron	N/A	NP_067638.3
	TRPV4	NM_001177431.1		c.1051-10C>T		intron	N/A	NP_001170902.1	Q9HBA0-5
	TRPV4	NM_001177428.1		c.1012-10C>T		intron	N/A	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.1153-10C>T		intron	N/A	ENSP00000261740.2	Q9HBA0-1
	TRPV4	ENST00000418703.7	TSL:1	c.1153-10C>T		intron	N/A	ENSP00000406191.2	Q9HBA0-1
	TRPV4	ENST00000536838.1	TSL:1	c.1051-10C>T		intron	N/A	ENSP00000444336.1	Q9HBA0-5

Frequencies

GnomAD3 genomes AF: 0.00553 AC: 842 AN: 152192 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00692

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00885

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00562 AC: 1388 AN: 246922 AF XY: 0.00606

Gnomad AFR exome AF: 0.000926

Gnomad AMR exome AF: 0.00276

Gnomad ASJ exome AF: 0.00744

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000957

Gnomad NFE exome AF: 0.00888

Gnomad OTH exome AF: 0.00663

GnomAD4 exome AF: 0.00758 AC: 11017 AN: 1453444 Hom.: 49 Cov.: 31 AF XY: 0.00755 AC XY: 5449 AN XY: 721564

African (AFR) AF: 0.00159 AC: 53 AN: 33336

American (AMR) AF: 0.00274 AC: 122 AN: 44534

Ashkenazi Jewish (ASJ) AF: 0.00717 AC: 185 AN: 25798

East Asian (EAS) AF: 0.00 AC: 0 AN: 39524

South Asian (SAS) AF: 0.00510 AC: 437 AN: 85694

European-Finnish (FIN) AF: 0.000948 AC: 50 AN: 52720

Middle Eastern (MID) AF: 0.00727 AC: 41 AN: 5636

European-Non Finnish (NFE) AF: 0.00883 AC: 9764 AN: 1106216

Other (OTH) AF: 0.00608 AC: 365 AN: 59986

GnomAD4 genome AF: 0.00553 AC: 843 AN: 152310 Hom.: 4 Cov.: 32 AF XY: 0.00545 AC XY: 406 AN XY: 74476

African (AFR) AF: 0.00173 AC: 72 AN: 41564

American (AMR) AF: 0.00673 AC: 103 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00692 AC: 24 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00476 AC: 23 AN: 4832

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10622

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00885 AC: 602 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00647 Hom.: 0

Bravo AF: 0.00592

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Charcot-Marie-Tooth disease axonal type 2C (2)
-	-	2	not provided (2)
-	-	1	Brachyrachia (short spine dysplasia) (1)
-	-	1	Charcot-Marie-Tooth disease (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)
-	-	1	Spondylometaphyseal dysplasia, Kozlowski type;C0265281:Metatropic dysplasia;C0432227:Brachyrachia (short spine dysplasia);C0751335:Scapuloperoneal spinal muscular atrophy;C1838492:Neuronopathy, distal hereditary motor, autosomal dominant 8;C1847406:Familial digital arthropathy-brachydactyly;C1853710:Charcot-Marie-Tooth disease axonal type 2C;C1868616:Parastremmatic dwarfism;C3150755:Sodium serum level quantitative trait locus 1;C3159322:Spondyloepimetaphyseal dysplasia, Maroteaux type;C4479260:Avascular necrosis of femoral head, primary, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.8
DANN	Benign	0.44
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0
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: rs149541389; hg19: chr12-110234519;