chr3-142684009-A-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001145319.2(PLS1):c.583A>C(p.Asn195His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000126 in 1,593,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
PLS1
NM_001145319.2 missense
NM_001145319.2 missense
Scores
15
2
1
Clinical Significance
Conservation
PhyloP100: 8.86
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 Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.99
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PLS1 | NM_001145319.2 | c.583A>C | p.Asn195His | missense_variant | 7/16 | ENST00000457734.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PLS1 | ENST00000457734.7 | c.583A>C | p.Asn195His | missense_variant | 7/16 | 2 | NM_001145319.2 | P1 | |
ENST00000690164.1 | n.119-26803T>G | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152062Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000426 AC: 1AN: 234630Hom.: 0 AF XY: 0.00000788 AC XY: 1AN XY: 126962
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GnomAD4 exome AF: 6.94e-7 AC: 1AN: 1441496Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1AN XY: 716244
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GnomAD4 genome ? AF: 0.00000658 AC: 1AN: 152062Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74266
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
PLS1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 23, 2023 | The PLS1 c.583A>C variant is predicted to result in the amino acid substitution p.Asn195His. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0016% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-142402851-A-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Uncertain
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
Uncertain
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 helix (P = 0.132);.;Gain of helix (P = 0.132);Gain of helix (P = 0.132);
MVP
MPC
0.72
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at