Genetic Variant NM_001142864.4:c.2263G>A (chr16-88733972-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001142864.4(PIEZO1):c.2263G>A(p.Glu755Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,395,936 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.480

Publications

4 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10482526).

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.2263G>A	p.Glu755Lys	missense	Exon 17 of 51	NP_001136336.2
	HSALR1	NR_103774.1		n.269+2524C>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.2263G>A	p.Glu755Lys	missense	Exon 17 of 51	ENSP00000301015.9
PIEZO1	ENST00000938928.1		c.2263G>A	p.Glu755Lys	missense	Exon 17 of 51	ENSP00000608987.1
HSALR1	ENST00000440406.2	TSL:2	n.269+2524C>T		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000137

AC:

AN:

145798

AF XY:

0.0000128

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:

0.0000373

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000287

AC:

AN:

1395936

Hom.:

Cov.:

AF XY:

0.00000436

AC XY:

AN XY:

688354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31364

American (AMR)

AF:

0.00

AC:

AN:

35612

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25108

East Asian (EAS)

AF:

0.00

AC:

AN:

35692

South Asian (SAS)

AF:

0.00

AC:

AN:

79100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

0.00000278

AC:

AN:

1077644

Other (OTH)

AF:

0.0000173

AC:

AN:

57922

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

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:

0.0000470

Hom.:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0092

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.34

LIST_S2

Benign

0.50

M_CAP

Pathogenic

0.44

MetaRNN

Benign

0.10

MetaSVM

Benign

-0.81

MutationAssessor

Benign

1.8

PhyloP100

-0.48

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.8

REVEL

Benign

0.17

Sift

Benign

0.43

Sift4G

Benign

0.091

Polyphen

0.020

Vest4

0.28

MutPred

0.20

Gain of ubiquitination at E755 (P = 0.0051)

MVP

0.068

ClinPred

0.20

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.3

Varity_R

0.14

gMVP

0.30

Mutation Taster

=91/9

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over