chr3-142676175-T-C
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_001145319.2(PLS1):c.383T>C(p.Phe128Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).
Frequency
Genomes: not found (cov: 32)
Consequence
PLS1
NM_001145319.2 missense
NM_001145319.2 missense
Scores
16
1
1
Clinical Significance
Conservation
PhyloP100: 8.02
Genes affected
PLS1 (HGNC:9090): (plastin 1) Plastins are a family of actin-binding proteins that are conserved throughout eukaryote evolution and expressed in most tissues of higher eukaryotes. In humans, two ubiquitous plastin isoforms (L and T) have been identified. The protein encoded by this gene is a third distinct plastin isoform, which is specifically expressed at high levels in the small intestine. Alternatively spliced transcript variants varying in the 5' UTR, but encoding the same protein, have been found for this gene. A pseudogene of this gene is found on chromosome 11.[provided by RefSeq, Feb 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.921
PP5
?
Variant 3-142676175-T-C is Pathogenic according to our data. Variant chr3-142676175-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 633603.Status of the report is no_assertion_criteria_provided, 0 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLS1 | NM_001145319.2 | c.383T>C | p.Phe128Ser | missense_variant | 5/16 | ENST00000457734.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLS1 | ENST00000457734.7 | c.383T>C | p.Phe128Ser | missense_variant | 5/16 | 2 | NM_001145319.2 | P1 | |
ENST00000690164.1 | n.119-18969A>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
GnomAD4 exome Cov.: 30
GnomAD4 exome
Cov.:
30
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: no assertion criteria provided
LINK: link
Submissions by phenotype
Bilateral sensorineural hearing impairment;C5779548:Autosomal dominant nonsyndromic hearing loss Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Laboratory of Molecular Genetics, Montpellier University Hospital | May 29, 2019 | The p.(Phe128Ser) variant in PLS1 has been reported in 3 individuals of the same family (3 generations) presenting with the phenotype. The variant is absent from large population studies and predicted to possibly alter the structure of the protein. It is then considered as likely pathogenic. - |
Hearing loss, autosomal dominant 76 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Feb 21, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Pathogenic
D;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.;H;H
MutationTaster
Benign
D;D;D
PrimateAI
Pathogenic
T
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Pathogenic
D;D;D;D
Polyphen
D;.;D;D
Vest4
MutPred
Gain of disorder (P = 0.003);.;Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);
MVP
MPC
1.0
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at