chr16-88715641-C-T

Position:

• chr16-88715641-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001142864.4(PIEZO1):​c.7530G>A​(p.Pro2510=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,550,234 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0075 (11 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (19 hom.)
• Consequence: PIEZO1 NM_001142864.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.68

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=0.0023759902).
• BP6: Variant 16-88715641-C-T is Benign according to our data. Variant chr16-88715641-C-T is described in ClinVar as [Benign]. Clinvar id is 789647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-88715641-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-4.68 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00745 (1135/152328) while in subpopulation AFR AF= 0.0251 (1042/41574). AF 95% confidence interval is 0.0238. There are 11 homozygotes in gnomad4. There are 562 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1135 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PIEZO1	NM_001142864.4	c.7530G>A	p.Pro2510=	synonymous_variant	51/51	ENST00000301015.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PIEZO1	ENST00000301015.14	c.7530G>A	p.Pro2510=	synonymous_variant	51/51	1	NM_001142864.4	P1

Frequencies

GnomAD3 genomes AF: 0.00744 AC: 1132 AN: 152210 Hom.: 11 Cov.: 33

Gnomad AFR AF: 0.0251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00438

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00175 AC: 270 AN: 154470 Hom.: 2 AF XY: 0.00134 AC XY: 110 AN XY: 82116

Gnomad AFR exome AF: 0.0294

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.000119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000176

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000102

Gnomad OTH exome AF: 0.000917

GnomAD4 exome AF: 0.000874 AC: 1222 AN: 1397906 Hom.: 19 Cov.: 32 AF XY: 0.000719 AC XY: 496 AN XY: 689454

Gnomad4 AFR exome AF: 0.0293

Gnomad4 AMR exome AF: 0.00162

Gnomad4 ASJ exome AF: 0.0000397

Gnomad4 EAS exome AF: 0.0000280

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000871

Gnomad4 OTH exome AF: 0.00217

GnomAD4 genome AF: 0.00745 AC: 1135 AN: 152328 Hom.: 11 Cov.: 33 AF XY: 0.00754 AC XY: 562 AN XY: 74490

Gnomad4 AFR AF: 0.0251

Gnomad4 AMR AF: 0.00438

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00239 Hom.: 3

Bravo AF: 0.00918

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0275 AC: 38

ESP6500EA AF: 0.000315 AC: 1

ExAC AF: 0.00296 AC: 76

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 22, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 13, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	0.079
DANN	Benign	0.90
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.074	N
LIST_S2	Benign	0.36	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.98	T
MutationTaster	Benign	1.0	D;N
PROVEAN	Benign	2.3	N
REVEL	Benign	0.15
Sift	Pathogenic	0.0	D
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.16		Loss of relative solvent accessibility (P = 0.0404);
MVP		0.043
ClinPred		0.012	T
GERP RS		-9.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs115423293; hg19: chr16-88782049;