16-88715676-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001142864.4(PIEZO1):c.7495T>C(p.Leu2499=) variant causes a synonymous change. The variant allele was found at a frequency of 0.000481 in 1,549,806 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00027 (1 hom.)
• Consequence: PIEZO1 NM_001142864.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.10

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003376186).
• BP6: Variant 16-88715676-A-G is Benign according to our data. Variant chr16-88715676-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 727409.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00243 (369/151812) while in subpopulation AFR AF= 0.00839 (347/41382). AF 95% confidence interval is 0.00766. There are 2 homozygotes in gnomad4. There are 177 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 368 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO1	NM_001142864.4	c.7495T>C	p.Leu2499=	synonymous_variant	51/51	ENST00000301015.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO1	ENST00000301015.14	c.7495T>C	p.Leu2499=	synonymous_variant	51/51	1	NM_001142864.4	P1

Frequencies

GnomAD3 genomes AF: 0.00243 AC: 368 AN: 151694 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00839

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000788

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00384

GnomAD3 exomes AF: 0.000636 AC: 99 AN: 155670 Hom.: 1 AF XY: 0.000496 AC XY: 41 AN XY: 82678

Gnomad AFR exome AF: 0.00992

Gnomad AMR exome AF: 0.000649

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000334

Gnomad OTH exome AF: 0.000456

GnomAD4 exome AF: 0.000270 AC: 377 AN: 1397994 Hom.: 1 Cov.: 35 AF XY: 0.000231 AC XY: 159 AN XY: 689484

Gnomad4 AFR exome AF: 0.00934

Gnomad4 AMR exome AF: 0.000644

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000834

Gnomad4 OTH exome AF: 0.000810

GnomAD4 genome AF: 0.00243 AC: 369 AN: 151812 Hom.: 2 Cov.: 33 AF XY: 0.00239 AC XY: 177 AN XY: 74154

Gnomad4 AFR AF: 0.00839

Gnomad4 AMR AF: 0.000787

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00380

Alfa AF: 0.00139 Hom.: 0

Bravo AF: 0.00293

ExAC AF: 0.000907 AC: 24

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely 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	Invitae	Nov 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	May 29, 2020	- -

Lymphatic malformation 6;C4551512:Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 27, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.060
Cadd	Benign	5.5
Dann	Benign	0.89
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	1.3	N
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D
Polyphen		0.0	B
Vest4		0.066
MVP		0.043
ClinPred		0.051	T
GERP RS		0.91
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9

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: rs35736353; hg19: chr16-88782084;