chr16-88722285-C-A

Variant names:

• chr16-88722285-C-A
• rs869025597
• NM_001142864.4:c.4888G>T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000301015.14(PIEZO1):​c.4888G>T​(p.Glu1630*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 34)
• Consequence: PIEZO1 ENST00000301015.14 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.65
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• PIEZO1-related generalized lymphatic dysplasia with non-immune hydrops fetalis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema

  Inheritance: AD Classification: STRONG Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
• lymphatic malformation 6

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• dehydrated hereditary stomatocytosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-88722285-C-A is Pathogenic according to our data. Variant chr16-88722285-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 223128.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000301015.14. 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.4888G>T	p.Glu1630*	stop_gained	Exon 36 of 51	NP_001136336.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.4888G>T	p.Glu1630*	stop_gained	Exon 36 of 51	ENSP00000301015.9
	PIEZO1	ENST00000566414.1	TSL:4	n.*238G>T		downstream_gene	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 34

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Lymphatic malformation 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	38
DANN	Uncertain	0.99
Eigen	Uncertain	0.34
Eigen_PC	Benign	0.0015
FATHMM_MKL	Benign	0.22	N
PhyloP100		1.7
Vest4		0.34
ClinPred		0.99	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs869025597; hg19: chr16-88788693;