16-88733731-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001142864.4(PIEZO1):c.2344G>A(p.Gly782Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00514 in 1,545,466 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0040 ( 2 hom., cov: 34)

Exomes 𝑓: 0.0053 ( 33 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:5

Conservation

PhyloP100: 3.99

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:

ENSG00000224888 (HGNC:56095): (HSP90AB1 associated lncRNA 1)

ENSG00000224888 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011941671).

BP6

Variant 16-88733731-C-T is Benign according to our data. Variant chr16-88733731-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 242665.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr16-88733731-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00402 (612/152324) while in subpopulation NFE AF= 0.00625 (425/68020). AF 95% confidence interval is 0.00576. There are 2 homozygotes in gnomad4. There are 269 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High AC in GnomAd4 at 612 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4 link	c.2344G>A	p.Gly782Ser	missense_variant	Exon 18 of 51	ENST00000301015.14	NP_001136336.2	Q92508
HSALR1	NR_103774.1 link	n.269+2283C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14 link	c.2344G>A	p.Gly782Ser	missense_variant	Exon 18 of 51	1	NM_001142864.4	ENSP00000301015.9		Q92508
ENSG00000224888	ENST00000440406.2 link	n.269+2283C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.00402

AC:

612

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000989

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00790

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00625

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00381

AC:

554

AN:

145236

Hom.:

AF XY:

0.00376

AC XY:

293

AN XY:

78020

show subpopulations

Gnomad AFR exome

AF:

0.000863

Gnomad AMR exome

AF:

0.00108

Gnomad ASJ exome

AF:

0.00312

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00100

Gnomad FIN exome

AF:

0.00817

Gnomad NFE exome

AF:

0.00627

Gnomad OTH exome

AF:

0.00264

GnomAD4 exome

AF:

0.00526

AC:

7329

AN:

1393142

Hom.:

Cov.:

AF XY:

0.00507

AC XY:

3484

AN XY:

686826

show subpopulations

Gnomad4 AFR exome

AF:

0.000761

Gnomad4 AMR exome

AF:

0.00130

Gnomad4 ASJ exome

AF:

0.00302

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000992

Gnomad4 FIN exome

AF:

0.00949

Gnomad4 NFE exome

AF:

0.00591

Gnomad4 OTH exome

AF:

0.00493

GnomAD4 genome

AF:

0.00402

AC:

612

AN:

152324

Hom.:

Cov.:

AF XY:

0.00361

AC XY:

269

AN XY:

74490

show subpopulations

Gnomad4 AFR

AF:

0.000986

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00790

Gnomad4 NFE

AF:

0.00625

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.00548

Hom.:

Bravo

AF:

0.00342

TwinsUK

AF:

0.00674

AC:

ALSPAC

AF:

0.00415

AC:

ExAC

AF:

0.00198

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:4

Nov 11, 2022

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

BS2, BP4, PP1 -

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 15, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Dec 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PIEZO1: BS2 -

not specified

Uncertain:1

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Lymphatic malformation 6

Uncertain:1

May 28, 2019

Mendelics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PIEZO1-related disorder

Benign:1

Jul 23, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0069

Eigen

Uncertain

0.42

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.85

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.5

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-2.0

REVEL

Benign

0.18

Sift

Benign

0.41

Sift4G

Benign

0.57

Polyphen

1.0

Vest4

0.90

MVP

0.15

ClinPred

0.035

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

gMVP

0.42

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over