16-88731795-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001142864.4(PIEZO1):c.3107G>A(p.Arg1036His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000962 in 1,549,026 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 29)

Exomes 𝑓: 0.000098 ( 2 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 0.538

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 links:

ENSG00000224888 (HGNC:56095): (HSP90AB1 associated lncRNA 1)

ENSG00000224888 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26031417).

BS2

High AC in GnomAd4 at 12 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4 link	c.3107G>A	p.Arg1036His	missense_variant	Exon 22 of 51	ENST00000301015.14	NP_001136336.2	Q92508
HSALR1	NR_103774.1 link	n.269+347C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14 link	c.3107G>A	p.Arg1036His	missense_variant	Exon 22 of 51	1	NM_001142864.4	ENSP00000301015.9		Q92508
ENSG00000224888	ENST00000440406.2 link	n.269+347C>T		intron_variant	Intron 1 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000794

AC:

AN:

151066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000488

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000199

Gnomad SAS

AF:

0.000629

Gnomad FIN

AF:

0.0000951

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000737

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000129

AC:

AN:

154844

Hom.:

AF XY:

0.000146

AC XY:

AN XY:

82356

show subpopulations

Gnomad AFR exome

AF:

0.000128

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000351

Gnomad FIN exome

AF:

0.000186

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.000229

GnomAD4 exome

AF:

0.0000980

AC:

137

AN:

1397842

Hom.:

Cov.:

AF XY:

0.000106

AC XY:

AN XY:

689422

show subpopulations

Gnomad4 AFR exome

AF:

0.0000317

Gnomad4 AMR exome

AF:

0.0000840

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000265

Gnomad4 FIN exome

AF:

0.000438

Gnomad4 NFE exome

AF:

0.0000732

Gnomad4 OTH exome

AF:

0.000172

GnomAD4 genome

AF:

0.0000794

AC:

AN:

151184

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

73836

show subpopulations

Gnomad4 AFR

AF:

0.0000487

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000199

Gnomad4 SAS

AF:

0.000630

Gnomad4 FIN

AF:

0.0000951

Gnomad4 NFE

AF:

0.0000737

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.000188

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3107G>A (p.R1036H) alteration is located in exon 22 (coding exon 22) of the PIEZO1 gene. This alteration results from a G to A substitution at nucleotide position 3107, causing the arginine (R) at amino acid position 1036 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Lymphatic malformation 6

Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:1

Feb 11, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The PIEZO1 c.3107G>A; p.Arg1036His variant (rs769506340), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 548456). This variant is found in the general population with an overall allele frequency of 0.01% (21/185990 alleles) in the Genome Aggregation Database. The arginine at codon 1036 is moderately conserved, and computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.226). Given the lack of clinical and functional data, the significance of the p.Arg1036His variant is uncertain at this time. -

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

Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.017

Eigen

Benign

0.018

Eigen_PC

Benign

-0.10

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.63

MetaRNN

Benign

0.26

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.31

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.23

Sift

Benign

0.032

Sift4G

Uncertain

0.028

Polyphen

1.0

Vest4

0.17

MVP

0.36

ClinPred

0.22

GERP RS

3.3

Varity_R

0.14

gMVP

0.49

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over