rs769506340

Variant names:

• chr16-88731795-C-T
• rs769506340
• NM_001142864.4:c.3107G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-88731795-C-T
• chr16-88731795-C-A
• chr16-88731795-C-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001142864.4(PIEZO1):​c.3107G>A​(p.Arg1036His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000962 in 1,549,026 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1036C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000098 (2 hom.)
• Consequence: PIEZO1 NM_001142864.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.538
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.26031417).
• BS2: High Homozygotes in GnomAdExome4 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.3107G>A	p.Arg1036His	missense	Exon 22 of 51	NP_001136336.2	Q92508
	HSALR1	NR_103774.1		n.269+347C>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.3107G>A	p.Arg1036His	missense	Exon 22 of 51	ENSP00000301015.9	Q92508
	PIEZO1	ENST00000938928.1		c.3107G>A	p.Arg1036His	missense	Exon 22 of 51	ENSP00000608987.1
	HSALR1	ENST00000440406.2	TSL:2	n.269+347C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000794 AC: 12 AN: 151066 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.0000488

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.000629

Gnomad FIN AF: 0.0000951

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000737

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000129 AC: 20 AN: 154844 AF XY: 0.000146

Gnomad AFR exome AF: 0.000128

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.000117

Gnomad OTH exome AF: 0.000229

GnomAD4 exome AF: 0.0000980 AC: 137 AN: 1397842 Hom.: 2 Cov.: 33 AF XY: 0.000106 AC XY: 73 AN XY: 689422

African (AFR) AF: 0.0000317 AC: 1 AN: 31592

American (AMR) AF: 0.0000840 AC: 3 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25178

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35736

South Asian (SAS) AF: 0.000265 AC: 21 AN: 79236

European-Finnish (FIN) AF: 0.000438 AC: 21 AN: 47932

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5694

European-Non Finnish (NFE) AF: 0.0000732 AC: 79 AN: 1078802

Other (OTH) AF: 0.000172 AC: 10 AN: 57974

GnomAD4 genome AF: 0.0000794 AC: 12 AN: 151184 Hom.: 0 Cov.: 29 AF XY: 0.000108 AC XY: 8 AN XY: 73836

African (AFR) AF: 0.0000487 AC: 2 AN: 41086

American (AMR) AF: 0.00 AC: 0 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.000199 AC: 1 AN: 5024

South Asian (SAS) AF: 0.000630 AC: 3 AN: 4762

European-Finnish (FIN) AF: 0.0000951 AC: 1 AN: 10520

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000737 AC: 5 AN: 67838

Other (OTH) AF: 0.00 AC: 0 AN: 2098

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.000188 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	Lymphatic malformation 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.017	T
Eigen	Benign	0.018
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.63	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.54
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.23
Sift	Benign	0.032	D
Sift4G	Uncertain	0.028	D
Polyphen		1.0	D
Vest4		0.17
MVP		0.36
ClinPred		0.22	T
GERP RS		3.3
Varity_R		0.14
gMVP		0.49
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs769506340; hg19: chr16-88798203; COSMIC: COSV56339903; COSMIC: COSV56339903;