16-88715676-ACTC-A

Variant names:

• chr16-88715676-ACTC-A
• rs1468458581
• NM_001142864.4:c.7492_7494delGAG

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP5_Moderate BP3 BS2

The NM_001142864.4(PIEZO1):​c.7492_7494delGAG​(p.Glu2498del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000968 in 1,549,688 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: PIEZO1 NM_001142864.4 conservative_inframe_deletion
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.79

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 Likely_benign. Variant got -3 ACMG points.

• PP5: Variant 16-88715676-ACTC-A is Pathogenic according to our data. Variant chr16-88715676-ACTC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3376919.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP3: Nonframeshift variant in repetitive region in NM_001142864.4
• BS2: High AC in GnomAdExome4 at 14 AD,BG gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PIEZO1	NM_001142864.4	c.7492_7494delGAG	p.Glu2498del	conservative_inframe_deletion	Exon 51 of 51	ENST00000301015.14	NP_001136336.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PIEZO1	ENST00000301015.14	c.7492_7494delGAG	p.Glu2498del	conservative_inframe_deletion	Exon 51 of 51	1	NM_001142864.4	ENSP00000301015.9

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151694 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000100 AC: 14 AN: 1397994 Hom.: 0 AF XY: 0.0000102 AC XY: 7 AN XY: 689484

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000130

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151694 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74026

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lymphatic malformation 6 Pathogenic:1

Jul 17, 2023

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Likely pathogenic. Following criteria are met: 0103 - Loss of function and gain of function are known mechanisms of disease in this gene and are associated with lymphatic malformation 6 (LMPHM6; MIM#616843), and dehydrated hereditary stomatocytosis with or without pseudohyperkalaemia and/or perinatal oedema (DHS; MIM#194380), respectively (OMIM). (I) 0108 - This gene is associated with both recessive and dominant disease. LMPHM6 has been reported in individuals with biallelic variants, while DHS has only been reported in individuals with heterozygous missense variants or inframe duplication variants with a gain of function mechanism (OMIM). (I) 0213 - In-frame insertion/deletion in a non-repetitive region that has high conservation. (SP) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD <0.01 for a recessive condition (v3: 1 heterozygote, 0 homozygotes). (SP) 0600 - Variant is located in the annotated Piezo_RRas_bdg domain (DECIPHER). (I) 0705 - No comparable variants have previous evidence for pathogenicity. (I) 0807 - This variant has no previous evidence of pathogenicity. (I) 0902 - This variant has moderate evidence for segregation with disease. Three babies of this family that were shown homozygous presented hydrops and one heterozygous baby did not have hydrops. (SP) 1007 - No published functional evidence has been identified for this variant. (I) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by segregation analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

Computational scores

Source: dbNSFP v4.3

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: rs1468458581; hg19: chr16-88782084;