Genetic Variant PIEZO1:p.Thr2127Arg (chr16-88719665-G-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_001142864.4(PIEZO1):c.6380C>G(p.Thr2127Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000714 in 1,401,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T2127M) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.80

Publications

0 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: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: 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.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.923

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4 link	c.6380C>G	p.Thr2127Arg	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>G	p.Thr2127Arg	missense_variant	Exon 44 of 51	1	NM_001142864.4	ENSP00000301015.9		Q92508

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.14e-7

AC:

AN:

1401526

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

691620

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31678

American (AMR)

AF:

0.00

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:

0.00

AC:

AN:

79382

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48374

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

9.25e-7

AC:

AN:

1080858

Other (OTH)

AF:

0.00

AC:

AN:

58236

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

Eigen

Pathogenic

0.94

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

0.47

MutationAssessor

Pathogenic

3.2

PhyloP100

9.8

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.5

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.95

MutPred

0.46

Gain of solvent accessibility (P = 0.0171);

MVP

0.72

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.98

Mutation Taster

=25/75

disease causing

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over