rs185326407

Positions:

• chr16-88726747-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The ENST00000301015.14(PIEZO1):​c.3667G>A​(p.Val1223Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00402 in 1,549,974 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0028 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0042 (14 hom.)
• Consequence: PIEZO1 ENST00000301015.14 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.40

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00827384).
• BP6: Variant 16-88726747-C-T is Benign according to our data. Variant chr16-88726747-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 446042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88726747-C-T is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 431 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PIEZO1	NM_001142864.4	c.3667G>A	p.Val1223Ile	missense_variant	25/51	ENST00000301015.14	NP_001136336.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14	c.3667G>A	p.Val1223Ile	missense_variant	25/51	1	NM_001142864.4	ENSP00000301015	P1

Frequencies

GnomAD3 genomes AF: 0.00284 AC: 431 AN: 151998 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000991

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000473

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00475

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00281 AC: 428 AN: 152576 Hom.: 3 AF XY: 0.00279 AC XY: 227 AN XY: 81246

Gnomad AFR exome AF: 0.000889

Gnomad AMR exome AF: 0.00105

Gnomad ASJ exome AF: 0.0133

Gnomad EAS exome AF: 0.0000919

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.000262

Gnomad NFE exome AF: 0.00447

Gnomad OTH exome AF: 0.00301

GnomAD4 exome AF: 0.00415 AC: 5802 AN: 1397858 Hom.: 14 Cov.: 37 AF XY: 0.00408 AC XY: 2812 AN XY: 689446

Gnomad4 AFR exome AF: 0.000728

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.0109

Gnomad4 EAS exome AF: 0.000476

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.000563

Gnomad4 NFE exome AF: 0.00482

Gnomad4 OTH exome AF: 0.00330

GnomAD4 genome AF: 0.00283 AC: 431 AN: 152116 Hom.: 3 Cov.: 33 AF XY: 0.00269 AC XY: 200 AN XY: 74344

Gnomad4 AFR AF: 0.000988

Gnomad4 AMR AF: 0.00150

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000473

Gnomad4 NFE AF: 0.00475

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00441 Hom.: 0

Bravo AF: 0.00275

TwinsUK AF: 0.00593 AC: 22

ALSPAC AF: 0.00701 AC: 27

ESP6500AA AF: 0.000723 AC: 1

ESP6500EA AF: 0.00315 AC: 10

ExAC AF: 0.00261 AC: 66

ClinVar

Significance: Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 30, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 08, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	PIEZO1: BS2 -

PIEZO1-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 06, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Lymphatic malformation 6 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetics and Molecular Pathology, SA Pathology

May 19, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.017	T
Eigen	Benign	0.097
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.044	D
MetaRNN	Benign	0.0083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.77	N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.70	N
REVEL	Benign	0.050
Sift	Benign	0.20	T
Sift4G	Benign	0.16	T
Polyphen		0.76	P
Vest4		0.28
MVP		0.068
ClinPred		0.0085	T
GERP RS		4.5
Varity_R		0.040
gMVP		0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs185326407; hg19: chr16-88793155;