NM_001142864.4:c.2344G>A

Variant names:

• chr16-88733731-C-T
• rs200970763
• NM_001142864.4:c.2344G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001142864.4(PIEZO1):​c.2344G>A​(p.Gly782Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00514 in 1,545,466 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G782D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0040 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0053 (33 hom.)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:5
• Conservation: PhyloP100: 3.99
• Publications: 18 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]

HSALR1 (HGNC:56095): (HSP90AB1 associated lncRNA 1)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011941671).
• BP6: Variant 16-88733731-C-T is Benign according to our data. Variant chr16-88733731-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242665.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00402 (612/152324) while in subpopulation NFE AF = 0.00625 (425/68020). AF 95% confidence interval is 0.00576. There are 2 homozygotes in GnomAd4. There are 269 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001142864.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	NM_001142864.4	MANE Select	c.2344G>A	p.Gly782Ser	missense	Exon 18 of 51	NP_001136336.2	Q92508
	HSALR1	NR_103774.1		n.269+2283C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PIEZO1	ENST00000301015.14	TSL:1 MANE Select	c.2344G>A	p.Gly782Ser	missense	Exon 18 of 51	ENSP00000301015.9	Q92508
	PIEZO1	ENST00000938928.1		c.2344G>A	p.Gly782Ser	missense	Exon 18 of 51	ENSP00000608987.1
	HSALR1	ENST00000440406.2	TSL:2	n.269+2283C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 612 AN: 152206 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00790

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00625

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00381 AC: 554 AN: 145236 AF XY: 0.00376

Gnomad AFR exome AF: 0.000863

Gnomad AMR exome AF: 0.00108

Gnomad ASJ exome AF: 0.00312

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00817

Gnomad NFE exome AF: 0.00627

Gnomad OTH exome AF: 0.00264

GnomAD4 exome AF: 0.00526 AC: 7329 AN: 1393142 Hom.: 33 Cov.: 32 AF XY: 0.00507 AC XY: 3484 AN XY: 686826

African (AFR) AF: 0.000761 AC: 24 AN: 31520

American (AMR) AF: 0.00130 AC: 46 AN: 35270

Ashkenazi Jewish (ASJ) AF: 0.00302 AC: 75 AN: 24860

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35682

South Asian (SAS) AF: 0.000992 AC: 78 AN: 78650

European-Finnish (FIN) AF: 0.00949 AC: 451 AN: 47526

Middle Eastern (MID) AF: 0.00248 AC: 14 AN: 5652

European-Non Finnish (NFE) AF: 0.00591 AC: 6355 AN: 1076200

Other (OTH) AF: 0.00493 AC: 285 AN: 57782

GnomAD4 genome AF: 0.00402 AC: 612 AN: 152324 Hom.: 2 Cov.: 34 AF XY: 0.00361 AC XY: 269 AN XY: 74490

African (AFR) AF: 0.000986 AC: 41 AN: 41574

American (AMR) AF: 0.00157 AC: 24 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5178

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00790 AC: 84 AN: 10628

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00625 AC: 425 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00543 Hom.: 4

Bravo AF: 0.00342

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00415 AC: 16

ExAC AF: 0.00198 AC: 54

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	4	not provided (6)
-	1	-	Lymphatic malformation 6 (1)
-	1	-	not specified (1)
-	-	1	PIEZO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0069	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		4.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.18
Sift	Benign	0.41	T
Sift4G	Benign	0.57	T
Polyphen		1.0	D
Vest4		0.90
MVP		0.15
ClinPred		0.035	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.17
gMVP		0.42
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs200970763; hg19: chr16-88800139; COSMIC: COSV56333231; COSMIC: COSV56333231;