rs869025598

chr16-88716877-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001142864.4(PIEZO1):c.6682C>T(p.Gln2228Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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: 35)
• Consequence: PIEZO1 NM_001142864.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.40

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 16-88716877-G-A is Pathogenic according to our data. Variant chr16-88716877-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 223129.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr16-88716877-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO1	NM_001142864.4	c.6682C>T	p.Gln2228Ter	stop_gained	46/51	ENST00000301015.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO1	ENST00000301015.14	c.6682C>T	p.Gln2228Ter	stop_gained	46/51	1	NM_001142864.4	P1
PIEZO1	ENST00000419505.5	c.*260C>T		3_prime_UTR_variant, NMD_transcript_variant	5/10	1
PIEZO1	ENST00000327397.8	c.286C>T	p.Gln96Ter	stop_gained	3/8	2
PIEZO1	ENST00000484567.6	n.1741C>T		non_coding_transcript_exon_variant	2/7	2

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 35

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Lymphatic malformation 6 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 20, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.58
Cadd	Pathogenic	57
Dann	Uncertain	1.0
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A
Vest4		0.83
ClinPred		1.0	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs869025598; hg19: chr16-88783285;