16-88733652-C-T

Variant names:

• chr16-88733652-C-T
• rs202103485
• NM_001142864.4:c.2423G>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.2423G>A​(p.Arg808Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00519 in 1,549,762 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).

• Frequency:
  • Genomes: 𝑓 0.0041 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0053 (33 hom.)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 7.75
• Publications: 17 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=0.02918768).
• BP6: Variant 16-88733652-C-T is Benign according to our data. Variant chr16-88733652-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 242664.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00406 (619/152340) while in subpopulation NFE AF = 0.00628 (427/68016). AF 95% confidence interval is 0.00579. There are 2 homozygotes in GnomAd4. There are 275 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.2423G>A	p.Arg808Gln	missense	Exon 18 of 51	NP_001136336.2	Q92508
	HSALR1	NR_103774.1		n.269+2204C>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.2423G>A	p.Arg808Gln	missense	Exon 18 of 51	ENSP00000301015.9	Q92508
	PIEZO1	ENST00000938928.1		c.2423G>A	p.Arg808Gln	missense	Exon 18 of 51	ENSP00000608987.1
	HSALR1	ENST00000440406.2	TSL:2	n.269+2204C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00407 AC: 619 AN: 152222 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00790

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00628

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00383 AC: 577 AN: 150516 AF XY: 0.00382

Gnomad AFR exome AF: 0.000831

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00299

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00813

Gnomad NFE exome AF: 0.00628

Gnomad OTH exome AF: 0.00257

GnomAD4 exome AF: 0.00531 AC: 7420 AN: 1397422 Hom.: 33 Cov.: 32 AF XY: 0.00513 AC XY: 3533 AN XY: 689174

African (AFR) AF: 0.000728 AC: 23 AN: 31582

American (AMR) AF: 0.00132 AC: 47 AN: 35654

Ashkenazi Jewish (ASJ) AF: 0.00298 AC: 75 AN: 25154

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35732

South Asian (SAS) AF: 0.00109 AC: 86 AN: 79190

European-Finnish (FIN) AF: 0.00943 AC: 452 AN: 47926

Middle Eastern (MID) AF: 0.00246 AC: 14 AN: 5696

European-Non Finnish (NFE) AF: 0.00596 AC: 6432 AN: 1078540

Other (OTH) AF: 0.00500 AC: 290 AN: 57948

GnomAD4 genome AF: 0.00406 AC: 619 AN: 152340 Hom.: 2 Cov.: 33 AF XY: 0.00369 AC XY: 275 AN XY: 74486

African (AFR) AF: 0.00106 AC: 44 AN: 41582

American (AMR) AF: 0.00157 AC: 24 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5182

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4830

European-Finnish (FIN) AF: 0.00790 AC: 84 AN: 10630

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

European-Non Finnish (NFE) AF: 0.00628 AC: 427 AN: 68016

Other (OTH) AF: 0.00473 AC: 10 AN: 2112

Alfa AF: 0.00507 Hom.: 5

Bravo AF: 0.00345

TwinsUK AF: 0.00674 AC: 25

ALSPAC AF: 0.00415 AC: 16

ExAC AF: 0.00239 AC: 64

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	-	not specified (1)
-	-	1	PIEZO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.088	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.82	D
MetaRNN	Benign	0.029	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		7.7
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.20
Sift	Benign	0.42	T
Sift4G	Benign	0.42	T
Polyphen		1.0	D
Vest4		0.86
MVP		0.17
ClinPred		0.051	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.13
gMVP		0.78
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs202103485; hg19: chr16-88800060; COSMIC: COSV56333219; COSMIC: COSV56333219;