16-88733731-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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

6
12

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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 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].
BS2
High AC in GnomAd4 at 612 AD,BG gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PIEZO1NM_001142864.4 linkuse as main transcriptc.2344G>A p.Gly782Ser missense_variant 18/51 ENST00000301015.14 NP_001136336.2 Q92508
HSALR1NR_103774.1 linkuse as main transcriptn.269+2283C>T intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PIEZO1ENST00000301015.14 linkuse as main transcriptc.2344G>A p.Gly782Ser missense_variant 18/511 NM_001142864.4 ENSP00000301015.9 Q92508
ENSG00000224888ENST00000440406.2 linkuse as main transcriptn.269+2283C>T intron_variant 2

Frequencies

GnomAD3 genomes
AF:
0.00402
AC:
612
AN:
152206
Hom.:
2
Cov.:
34
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.:
5
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.:
33
Cov.:
32
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.:
2
Cov.:
34
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.:
1
Bravo
AF:
0.00342
TwinsUK
AF:
0.00674
AC:
25
ALSPAC
AF:
0.00415
AC:
16
ExAC
AF:
0.00198
AC:
54
Asia WGS
AF:
0.000289
AC:
1
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
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024PIEZO1: BS2 -
Likely benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Likely benign, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesSep 02, 2023- -
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 17, 2023- -
Uncertain significance, criteria provided, single submitterclinical testingMayo Clinic Laboratories, Mayo ClinicNov 11, 2022BS2, BP4, PP1 -
not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCenter for Genomic Medicine, Rigshospitalet, Copenhagen University HospitalJul 31, 2024- -
Lymphatic malformation 6 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingMendelicsMay 28, 2019- -
PIEZO1-related disorder Benign:1
Likely benign, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJul 23, 2019This 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
T
BayesDel_noAF
Benign
-0.33
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0069
T
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.41
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.85
T
MetaRNN
Benign
0.012
T
MetaSVM
Benign
-0.86
T
MutationAssessor
Uncertain
2.5
M
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-2.0
N
REVEL
Benign
0.18
Sift
Benign
0.41
T
Sift4G
Benign
0.57
T
Polyphen
1.0
D
Vest4
0.90
MVP
0.15
ClinPred
0.035
T
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.

Other links and lift over

dbSNP: rs200970763; hg19: chr16-88800139; COSMIC: COSV56333231; COSMIC: COSV56333231; API