rs587776987

Variant names:

• chr16-88716885-A-C
• rs587776987
• NM_001142864.4:c.6674T>G
• PIEZO1 p.Met2225Arg

Your query was ambiguous. Multiple possible variants found:

• chr16-88716885-A-C
• chr16-88716885-A-G

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_001142864.4(PIEZO1):​c.6674T>G​(p.Met2225Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000000715 in 1,397,632 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.82
• Publications: 20 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: ClinGen, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• lymphatic malformation 6

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.899
• PP5: Variant 16-88716885-A-C is Pathogenic according to our data. Variant chr16-88716885-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 55805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.6674T>G	p.Met2225Arg	missense	Exon 46 of 51	NP_001136336.2	Q92508

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.6674T>G	p.Met2225Arg	missense	Exon 46 of 51	ENSP00000301015.9	Q92508
	PIEZO1	ENST00000419505.5	TSL:1	n.*252T>G		non_coding_transcript_exon	Exon 5 of 10	ENSP00000406358.1	H7C2J5
	PIEZO1	ENST00000419505.5	TSL:1	n.*252T>G		3_prime_UTR	Exon 5 of 10	ENSP00000406358.1	H7C2J5

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1397632 Hom.: 0 Cov.: 37 AF XY: 0.00000145 AC XY: 1 AN XY: 689312

African (AFR) AF: 0.00 AC: 0 AN: 31596

American (AMR) AF: 0.00 AC: 0 AN: 35704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078908

Other (OTH) AF: 0.00 AC: 0 AN: 57978

GnomAD4 genome Cov.: 34

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.59	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.034	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		5.8
PrimateAI	Uncertain	0.65	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.72
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.96
gMVP		0.97
Mutation Taster		=5/95	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs587776987;

hg19: chr16-88783293;