16-88715671-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001142864.4(PIEZO1):c.7500C>T(p.Tyr2500=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,550,144 control chromosomes in the GnomAD database, including 12,615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (1115 hom., cov: 33)
  • Exomes 𝑓: 0.12 (11500 hom.)
• Consequence: PIEZO1 NM_001142864.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.213

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0010708272).
• BP6: Variant 16-88715671-G-A is Benign according to our data. Variant chr16-88715671-G-A is described in ClinVar as [Benign]. Clinvar id is 381962.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88715671-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.213 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.155 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO1	NM_001142864.4	c.7500C>T	p.Tyr2500=	synonymous_variant	51/51	ENST00000301015.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO1	ENST00000301015.14	c.7500C>T	p.Tyr2500=	synonymous_variant	51/51	1	NM_001142864.4	P1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16333 AN: 152154 Hom.: 1117 Cov.: 33

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.276

Gnomad AMR AF: 0.161

Gnomad ASJ AF: 0.109

Gnomad EAS AF: 0.128

Gnomad SAS AF: 0.0749

Gnomad FIN AF: 0.140

Gnomad MID AF: 0.155

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.125

GnomAD3 exomes AF: 0.120 AC: 18677 AN: 155468 Hom.: 1222 AF XY: 0.117 AC XY: 9666 AN XY: 82564

Gnomad AFR exome AF: 0.0297

Gnomad AMR exome AF: 0.156

Gnomad ASJ exome AF: 0.109

Gnomad EAS exome AF: 0.118

Gnomad SAS exome AF: 0.0701

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.130

GnomAD4 exome AF: 0.124 AC: 173937 AN: 1397872 Hom.: 11500 Cov.: 36 AF XY: 0.123 AC XY: 84558 AN XY: 689418

Gnomad4 AFR exome AF: 0.0318

Gnomad4 AMR exome AF: 0.155

Gnomad4 ASJ exome AF: 0.111

Gnomad4 EAS exome AF: 0.171

Gnomad4 SAS exome AF: 0.0721

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.128

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.107 AC: 16335 AN: 152272 Hom.: 1115 Cov.: 33 AF XY: 0.109 AC XY: 8097 AN XY: 74450

Gnomad4 AFR AF: 0.0335

Gnomad4 AMR AF: 0.160

Gnomad4 ASJ AF: 0.109

Gnomad4 EAS AF: 0.128

Gnomad4 SAS AF: 0.0746

Gnomad4 FIN AF: 0.140

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.123

Alfa AF: 0.112 Hom.: 778

Bravo AF: 0.106

TwinsUK AF: 0.128 AC: 473

ALSPAC AF: 0.125 AC: 483

ExAC AF: 0.0847 AC: 2210

Asia WGS AF: 0.0990 AC: 344 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 21, 2015

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	0.25
Dann	Benign	0.90
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.79
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.91	P;P
PROVEAN	Benign	1.2	N
REVEL	Benign	0.080
Sift	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.28
ClinPred		0.022	T
GERP RS		-2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1061228; hg19: chr16-88782079; COSMIC: COSV56333057; COSMIC: COSV56333057;