rs587776991

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PP3_ModeratePP5_Very_Strong

The NM_001142864.4(PIEZO1):c.6380C>T(p.Thr2127Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000438 in 1,553,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T2127T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000045 ( 0 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: 9.80

Publications

14 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:

ENSG00000260121 (HGNC:):

ENSG00000260121 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.936

PP5

Variant 16-88719665-G-A is Pathogenic according to our data. Variant chr16-88719665-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55811.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.6380C>T	p.Thr2127Met	missense_variant	Exon 44 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.6380C>T	p.Thr2127Met	missense_variant	Exon 44 of 51	1	NM_001142864.4	ENSP00000301015.9		Q92508

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000366

AC:

AN:

163978

AF XY:

0.0000347

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000396

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000582

Gnomad NFE exome

AF:

0.0000463

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000450

AC:

AN:

1401526

Hom.:

Cov.:

AF XY:

0.0000492

AC XY:

AN XY:

691620

show subpopulations

African (AFR)

AF:

0.0000316

AC:

AN:

31678

American (AMR)

AF:

0.0000276

AC:

AN:

36176

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25204

East Asian (EAS)

AF:

0.00

AC:

AN:

35914

South Asian (SAS)

AF:

0.0000630

AC:

AN:

79382

European-Finnish (FIN)

AF:

0.0000207

AC:

AN:

48374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.0000509

AC:

AN:

1080858

Other (OTH)

AF:

0.00

AC:

AN:

58236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152200

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41452

American (AMR)

AF:

0.0000654

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68026

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000189

Hom.:

Bravo

AF:

0.0000302

ExAC

AF:

0.0000187

AC:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Aug 31, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PP1, PP3, PM2_moderate, PS3 -

Oct 18, 2022

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Pathogenic:2

May 09, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Feb 19, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Thr2127Met variant in PIEZO1 has been reported in two individuals with cli nical features of dehydrated hereditary stomatocytosis (Andolfo 2013, Albuisson 2013). The variant cosegregated with disease in one family in 16 relatives over three generations, including 4 obligate carriers (Andolfo 2013). This variant ha s been identified in 1/838 Latino chromosomes and 1/3490 Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587776991). In vitro functional studies provide some evidence that the p.Thr2 127Met variant may impact protein function by delaying inactivation time and the refore increasing cation transport (Albuisson 2103); however, these types of ass ays may not accurately represent biological function. In summary, although addit ional studies are required to fully establish its clinical significance, the p.T hr2127Met variant is likely pathogenic for dehydrated hereditary stomatocytosis in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_Strong; PM2; PS3 _Supporting -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.80

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Pathogenic

0.86

MetaRNN

Pathogenic

0.94

MetaSVM

Uncertain

0.57

MutationAssessor

Pathogenic

3.2

PhyloP100

9.8

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MVP

0.70

ClinPred

0.96

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.71

gMVP

0.93

Mutation Taster

=17/83

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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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