16-88727144-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001142864.4(PIEZO1):c.3350C>T(p.Ser1117Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000787 in 1,397,066 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000079 ( 0 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.0790

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: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4 link	c.3350C>T	p.Ser1117Leu	missense_variant	Exon 24 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.3350C>T	p.Ser1117Leu	missense_variant	Exon 24 of 51	1	NM_001142864.4	ENSP00000301015.9		Q92508
PIEZO1	ENST00000491917.2 link	n.336C>T		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000133

AC:

AN:

149816

AF XY:

0.0000125

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000787

AC:

AN:

1397066

Hom.:

Cov.:

AF XY:

0.00000581

AC XY:

AN XY:

688920

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31582

American (AMR)

AF:

0.00

AC:

AN:

35684

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25164

East Asian (EAS)

AF:

0.00

AC:

AN:

35708

South Asian (SAS)

AF:

0.00

AC:

AN:

79214

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47816

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5628

European-Non Finnish (NFE)

AF:

0.0000102

AC:

AN:

1078342

Other (OTH)

AF:

0.00

AC:

AN:

57928

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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.:

Alfa

AF:

0.0000410

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

PIEZO1-related disorder

Uncertain:1

Dec 21, 2023

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The PIEZO1 c.3350C>T variant is predicted to result in the amino acid substitution p.Ser1117Leu. This variant was reported with another variant in PIEZO1 in an individual with dehydrated hereditary stomatocytosis (Andolfo et al. 2013. PubMed ID: 23479567). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.50

CADD

Benign

5.8

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.010

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.83

M_CAP

Pathogenic

0.91

MetaRNN

Uncertain

0.56

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.6

PhyloP100

0.079

PrimateAI

Benign

0.39

PROVEAN

Benign

-2.2

REVEL

Benign

0.099

Sift

Benign

0.062

Sift4G

Uncertain

0.011

Polyphen

0.10

Vest4

0.69

MutPred

0.38

Gain of helix (P = 0.0325);

MVP

0.082

ClinPred

0.042

GERP RS

-1.3

Varity_R

0.044

gMVP

0.61

Mutation Taster

=31/69

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over