Genetic Variant NM_001142864.4:c.2344G>T (chr16-88733731-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001142864.4(PIEZO1):c.2344G>T(p.Gly782Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000718 in 1,393,148 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G782S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

PIEZO1
NM_001142864.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.99

Publications

18 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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.786

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	NM_001142864.4	MANE Select	c.2344G>T	p.Gly782Cys	missense	Exon 18 of 51	NP_001136336.2	Q92508
	HSALR1	NR_103774.1		n.269+2283C>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.2344G>T	p.Gly782Cys	missense	Exon 18 of 51	ENSP00000301015.9	Q92508
PIEZO1	ENST00000938928.1		c.2344G>T	p.Gly782Cys	missense	Exon 18 of 51	ENSP00000608987.1
HSALR1	ENST00000440406.2	TSL:2	n.269+2283C>A		intron	N/A

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

145236

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.18e-7

AC:

AN:

1393148

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

686828

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31520

American (AMR)

AF:

0.00

AC:

AN:

35270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24858

East Asian (EAS)

AF:

0.00

AC:

AN:

35682

South Asian (SAS)

AF:

0.00

AC:

AN:

78650

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5652

European-Non Finnish (NFE)

AF:

9.29e-7

AC:

AN:

1076208

Other (OTH)

AF:

0.00

AC:

AN:

57782

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Benign

-0.12

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.44

MutationAssessor

Uncertain

2.8

PhyloP100

4.0

PrimateAI

Uncertain

0.63

PROVEAN

Uncertain

-3.7

REVEL

Uncertain

0.35

Sift

Benign

0.18

Sift4G

Benign

0.19

Polyphen

1.0

Vest4

0.83

MutPred

0.42

Gain of helix (P = 0.0425)

MVP

0.15

ClinPred

0.99

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.39

gMVP

0.49

Mutation Taster

=52/48

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over