NM_001142864.4:c.3107G>A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -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. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1036C) has been classified 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:5

Conservation

PhyloP100: 0.538

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 links:

HSALR1 (HGNC:56095): (HSP90AB1 associated lncRNA 1)

HSALR1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142864.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	NM_001142864.4	MANE Select	c.3107G>A	p.Arg1036His	missense	Exon 22 of 51	NP_001136336.2
	HSALR1	NR_103774.1		n.269+347C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.3107G>A	p.Arg1036His	missense	Exon 22 of 51	ENSP00000301015.9
	HSALR1	ENST00000440406.2	TSL:2	n.269+347C>T		intron	N/A

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

GnomAD2 exomes

AF:

0.000129

AC:

AN:

154844

AF XY:

0.000146

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 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

African (AFR)

AF:

0.0000317

AC:

AN:

31592

American (AMR)

AF:

0.0000840

AC:

AN:

35698

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25178

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35736

South Asian (SAS)

AF:

0.000265

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.000438

AC:

AN:

47932

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.0000732

AC:

AN:

1078802

Other (OTH)

AF:

0.000172

AC:

AN:

57974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.473

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.0000794

AC:

AN:

151184

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

73836

show subpopulations

African (AFR)

AF:

0.0000487

AC:

AN:

41086

American (AMR)

AF:

0.00

AC:

AN:

15190

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000199

AC:

AN:

5024

South Asian (SAS)

AF:

0.000630

AC:

AN:

4762

European-Finnish (FIN)

AF:

0.0000951

AC:

AN:

10520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000737

AC:

AN:

67838

Other (OTH)

AF:

0.00

AC:

AN:

2098

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

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:

0.0000987

Hom.:

Bravo

AF:

0.000110

ExAC

AF:

0.000188

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Jun 25, 2024

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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.

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

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

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

PhyloP100

0.54

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

Mutation Taster

=83/17

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over