rs587776989

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_001142864.4(PIEZO1):c.6058G>A(p.Ala2020Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000215 in 1,398,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

2

15

2

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.41

Variant links:

Genes affected

PIEZO1 (HGNC:28993): (piezo type mechanosensitive ion channel component 1 (Er blood group)) The protein encoded by this gene is a mechanically-activated ion channel that links mechanical forces to biological signals. The encoded protein contains 36 transmembrane domains and functions as a homotetramer. Defects in this gene have been associated with dehydrated hereditary stomatocytosis. [provided by RefSeq, Jul 2015]

PIEZO1 links:

ENSG00000260121 (HGNC:):

ENSG00000260121 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.782

PP5

Variant 16-88720175-C-T is Pathogenic according to our data. Variant chr16-88720175-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 55807.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4 link	c.6058G>A	p.Ala2020Thr	missense_variant	Exon 42 of 51	ENST00000301015.14	NP_001136336.2	Q92508

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14 link	c.6058G>A	p.Ala2020Thr	missense_variant	Exon 42 of 51	1	NM_001142864.4	ENSP00000301015.9		Q92508

Frequencies

GnomAD3 genomes

Cov.:

33

GnomAD4 exome

AF:

0.00000215

AC:

3

AN:

1398174

Hom.:

0

Cov.:

33

AF XY:

0.00000145

AC XY:

1

AN XY:

689572

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.27e-7

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

Cov.:

33

Bravo

AF:

0.0000189

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Jun 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2020 of the PIEZO1 protein (p.Ala2020Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with dehydrated hereditary stomatocytosis (PMID: 23695678, 29952828). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 55807). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt PIEZO1 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Jul 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Published functional studies demonstrate an increase in the inactivation time compared to wild type channel kinetics, indicating that variant results in a gain-of-function (PMID: 23695678); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 29952828, 29449963, 28971506, 33181827, 9827909, 23695678, 17253968) -

Mar 10, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2, PS3, PP1_moderate -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 24, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIEZO1 c.6058G>A; p.Ala2020Thr variant (rs587776989, ClinVar Variation ID 55807) is reported in the literature in individuals affected with dehydrated hereditary spherocytosis (Albuisson 2013, Halma 2019). This variant is absent from the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. In vitro functional analyses demonstrate prolonged PIEZO1 channel activity consistent with gain-of-function (Albuisson 2013). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.592). Based on available information, this variant is considered to be likely pathogenic. References: Albuisson J et al. Dehydrated hereditary stomatocytosis linked to gain-of-function mutations in mechanically activated PIEZO1 ion channels. Nat Commun. 2013 PMID: 23695678. Halma J et al. Dehydrated Hereditary Stomatocytosis Presenting as Severe Perinatal Ascites and Cholestasis. J Pediatr Gastroenterol Nutr. 2019 Mar. PMID: 29952828. -

Feb 19, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema

Pathogenic:1

Jan 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Uncertain

0.15

D

BayesDel_noAF

Uncertain

-0.030

CADD

Uncertain

26

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

T

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Uncertain

0.96

D

LIST_S2

Uncertain

0.94

D

M_CAP

Pathogenic

0.77

D

MetaRNN

Pathogenic

0.78

D

MetaSVM

Uncertain

0.14

D

MutationAssessor

Uncertain

2.5

M

PrimateAI

Uncertain

0.69

T

PROVEAN

Uncertain

-3.8

D

REVEL

Uncertain

0.59

Sift

Uncertain

0.0030

D

Sift4G

Uncertain

0.024

D

Polyphen

0.94

P

Vest4

0.69

MutPred

0.34

Loss of helix (P = 0.0376);

MVP

0.33

ClinPred

0.99

D

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.56

gMVP

0.59

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs587776989; hg19: chr16-88786583;