16-88726747-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001142864.4(PIEZO1):c.3667G>A(p.Val1223Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,549,974 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 3 hom., cov: 33)

Exomes 𝑓: 0.0042 ( 14 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 2.40

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema
Inheritance: AD Classification: STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
lymphatic malformation 6
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
dehydrated hereditary stomatocytosis
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

PIEZO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.00827384).

BP6

Variant 16-88726747-C-T is Benign according to our data. Variant chr16-88726747-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 446042.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 = 0.00283 (431/152116) while in subpopulation NFE AF = 0.00475 (323/67976). AF 95% confidence interval is 0.00432. There are 3 homozygotes in GnomAd4. There are 200 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 3 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4 link	c.3667G>A	p.Val1223Ile	missense_variant	Exon 25 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.3667G>A	p.Val1223Ile	missense_variant	Exon 25 of 51	1	NM_001142864.4	ENSP00000301015.9		Q92508

Frequencies

GnomAD3 genomes

AF:

0.00284

AC:

431

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000991

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

Gnomad ASJ

AF:

0.0101

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000473

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00475

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.00281

AC:

428

AN:

152576

AF XY:

0.00279

show subpopulations

Gnomad AFR exome

AF:

0.000889

Gnomad AMR exome

AF:

0.00105

Gnomad ASJ exome

AF:

0.0133

Gnomad EAS exome

AF:

0.0000919

Gnomad FIN exome

AF:

0.000262

Gnomad NFE exome

AF:

0.00447

Gnomad OTH exome

AF:

0.00301

GnomAD4 exome

AF:

0.00415

AC:

5802

AN:

1397858

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

2812

AN XY:

689446

show subpopulations

African (AFR)

AF:

0.000728

AC:

AN:

31594

American (AMR)

AF:

0.00143

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.0109

AC:

274

AN:

25172

East Asian (EAS)

AF:

0.000476

AC:

AN:

35728

South Asian (SAS)

AF:

0.000151

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.000563

AC:

AN:

47940

Middle Eastern (MID)

AF:

0.000702

AC:

AN:

5698

European-Non Finnish (NFE)

AF:

0.00482

AC:

5203

AN:

1078824

Other (OTH)

AF:

0.00330

AC:

191

AN:

57966

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

282

563

845

1126

1408

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00283

AC:

431

AN:

152116

Hom.:

Cov.:

AF XY:

0.00269

AC XY:

200

AN XY:

74344

show subpopulations

African (AFR)

AF:

0.000988

AC:

AN:

41510

American (AMR)

AF:

0.00150

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0101

AC:

AN:

3472

East Asian (EAS)

AF:

0.000194

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.000473

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00475

AC:

323

AN:

67976

Other (OTH)

AF:

0.00142

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

119

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00396

Hom.:

Bravo

AF:

0.00275

TwinsUK

AF:

0.00593

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.000723

AC:

ESP6500EA

AF:

0.00315

AC:

ExAC

AF:

0.00261

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PIEZO1: BS2 -

Jan 16, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 30, 2017

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 21, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

PIEZO1-related disorder

Benign:1

Aug 06, 2020

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). -

Lymphatic malformation 6

Benign:1

May 19, 2020

Genetics and Molecular Pathology, SA Pathology

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.017

Eigen

Benign

0.097

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.044

MetaRNN

Benign

0.0083

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.77

PhyloP100

2.4

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.70

REVEL

Benign

0.050

Sift

Benign

0.20

Sift4G

Benign

0.16

Polyphen

0.76

Vest4

0.28

MVP

0.068

ClinPred

0.0085

GERP RS

4.5

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.040

gMVP

0.43

Mutation Taster

=95/5

polymorphism

(source)

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

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16-88726747-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over