rs10445033

Variant names:

• chr16-88774054-G-A
• rs10445033
• NM_001142864.4:c.64+10847C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001142864.4(PIEZO1):​c.64+10847C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 152,088 control chromosomes in the GnomAD database, including 20,823 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.50 (20823 hom., cov: 32)
• Consequence: PIEZO1 NM_001142864.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.521
• Publications: 31 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4	c.64+10847C>T		intron_variant	Intron 1 of 50	ENST00000301015.14	NP_001136336.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14	c.64+10847C>T		intron_variant	Intron 1 of 50	1	NM_001142864.4	ENSP00000301015.9

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75905 AN: 151970 Hom.: 20820 Cov.: 32

Gnomad AFR AF: 0.254

Gnomad AMI AF: 0.822

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.681

Gnomad EAS AF: 0.629

Gnomad SAS AF: 0.612

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.609

Gnomad OTH AF: 0.538

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.499 AC: 75921 AN: 152088 Hom.: 20823 Cov.: 32 AF XY: 0.499 AC XY: 37070 AN XY: 74340

African (AFR) AF: 0.254 AC: 10563 AN: 41506

American (AMR) AF: 0.485 AC: 7420 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.681 AC: 2364 AN: 3470

East Asian (EAS) AF: 0.629 AC: 3242 AN: 5156

South Asian (SAS) AF: 0.613 AC: 2949 AN: 4810

European-Finnish (FIN) AF: 0.558 AC: 5901 AN: 10566

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.609 AC: 41415 AN: 67976

Other (OTH) AF: 0.533 AC: 1126 AN: 2114

Alfa AF: 0.581 Hom.: 37620

Bravo AF: 0.486

Asia WGS AF: 0.571 AC: 1985 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.29
DANN	Benign	0.57
PhyloP100		-0.52
Mutation Taster		=100/0	polymorphism (auto)

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: rs10445033; hg19: chr16-88840462;