chr16-88725505-C-G

Variant names:

• chr16-88725505-C-G
• rs587776990
• NM_001142864.4:c.4073G>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001142864.4(PIEZO1):​c.4073G>C​(p.Arg1358Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,377,054 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1358C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.19
• Publications: 11 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.878
• PP5: Variant 16-88725505-C-G is Pathogenic according to our data. Variant chr16-88725505-C-G is described in ClinVar as Pathogenic. ClinVar VariationId is 55808.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	NM_001142864.4	MANE Select	c.4073G>C	p.Arg1358Pro	missense	Exon 29 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.4073G>C	p.Arg1358Pro	missense	Exon 29 of 51	ENSP00000301015.9
	PIEZO1	ENST00000938928.1		c.4073G>C	p.Arg1358Pro	missense	Exon 29 of 51	ENSP00000608987.1
	PIEZO1	ENST00000474606.1	TSL:4	c.164G>C	p.Arg55Pro	missense	Exon 3 of 7	ENSP00000428673.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377054 Hom.: 0 Cov.: 32 AF XY: 0.00000148 AC XY: 1 AN XY: 677124

African (AFR) AF: 0.00 AC: 0 AN: 31072

American (AMR) AF: 0.00 AC: 0 AN: 33960

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23802

East Asian (EAS) AF: 0.00 AC: 0 AN: 35298

South Asian (SAS) AF: 0.00 AC: 0 AN: 76628

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47340

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5600

European-Non Finnish (NFE) AF: 9.38e-7 AC: 1 AN: 1066320

Other (OTH) AF: 0.00 AC: 0 AN: 57034

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
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	0.96
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Benign	0.030
Eigen_PC	Benign	0.000085
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.91	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		1.2
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.85
MutPred		0.27		Gain of methylation at K1360 (P = 0.0373)
MVP		0.55
ClinPred		0.98	D
GERP RS		3.1
Varity_R		0.85
gMVP		0.76
Mutation Taster		=30/70	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs587776990; hg19: chr16-88791913;