rs587776991
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 10P and 1B. PP3_ModeratePP5_Very_StrongBS2_Supporting
The NM_001142864.4(PIEZO1):c.6380C>T(p.Thr2127Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000438 in 1,553,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T2127T) has been classified as Likely benign.
Frequency
Consequence
NM_001142864.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PIEZO1 | NM_001142864.4 | c.6380C>T | p.Thr2127Met | missense_variant | 44/51 | ENST00000301015.14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PIEZO1 | ENST00000301015.14 | c.6380C>T | p.Thr2127Met | missense_variant | 44/51 | 1 | NM_001142864.4 | P1 | |
ENST00000564984.1 | n.1051G>A | non_coding_transcript_exon_variant | 1/1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000329 AC: 5AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000366 AC: 6AN: 163978Hom.: 0 AF XY: 0.0000347 AC XY: 3AN XY: 86432
GnomAD4 exome AF: 0.0000450 AC: 63AN: 1401526Hom.: 0 Cov.: 32 AF XY: 0.0000492 AC XY: 34AN XY: 691620
GnomAD4 genome ? AF: 0.0000329 AC: 5AN: 152200Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74356
ClinVar
Submissions by phenotype
Dehydrated hereditary stomatocytosis with or without pseudohyperkalemia and/or perinatal edema Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Feb 19, 2018 | The p.Thr2127Met variant in PIEZO1 has been reported in two individuals with cli nical features of dehydrated hereditary stomatocytosis (Andolfo 2013, Albuisson 2013). The variant cosegregated with disease in one family in 16 relatives over three generations, including 4 obligate carriers (Andolfo 2013). This variant ha s been identified in 1/838 Latino chromosomes and 1/3490 Finnish chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587776991). In vitro functional studies provide some evidence that the p.Thr2 127Met variant may impact protein function by delaying inactivation time and the refore increasing cation transport (Albuisson 2103); however, these types of ass ays may not accurately represent biological function. In summary, although addit ional studies are required to fully establish its clinical significance, the p.T hr2127Met variant is likely pathogenic for dehydrated hereditary stomatocytosis in an autosomal dominant manner. ACMG/AMP Criteria applied: PP1_Strong; PM2; PS3 _Supporting - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 09, 2013 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Oct 18, 2022 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at