chr12-27647774-C-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_003622.4(PPFIBP1):c.403C>T(p.Arg135Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,610,308 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000019 ( 0 hom. )
Consequence
PPFIBP1
NM_003622.4 stop_gained
NM_003622.4 stop_gained
Scores
2
4
1
Clinical Significance
Conservation
PhyloP100: 2.34
Genes affected
PPFIBP1 (HGNC:9249): (PPFIA binding protein 1) The protein encoded by this gene is a member of the LAR protein-tyrosine phosphatase-interacting protein (liprin) family. Liprins interact with members of LAR family of transmembrane protein tyrosine phosphatases, which are known to be important for axon guidance and mammary gland development. It has been proposed that liprins are multivalent proteins that form complex structures and act as scaffolds for the recruitment and anchoring of LAR family of tyrosine phosphatases. This protein was found to interact with S100A4, a calcium-binding protein related to tumor invasiveness and metastasis. In vitro experiment demonstrated that the interaction inhibited the phosphorylation of this protein by protein kinase C and protein kinase CK2. Alternatively spliced transcript variants encoding distinct isoforms have been reported. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 12-27647774-C-T is Pathogenic according to our data. Variant chr12-27647774-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 1679180.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-27647774-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PPFIBP1 | NM_003622.4 | c.403C>T | p.Arg135Ter | stop_gained | 6/30 | ENST00000228425.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PPFIBP1 | ENST00000228425.11 | c.403C>T | p.Arg135Ter | stop_gained | 6/30 | 1 | NM_003622.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000132 AC: 2AN: 151986Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000283 AC: 7AN: 247526Hom.: 0 AF XY: 0.0000224 AC XY: 3AN XY: 133802
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GnomAD4 exome AF: 0.0000192 AC: 28AN: 1458322Hom.: 0 Cov.: 29 AF XY: 0.0000193 AC XY: 14AN XY: 725396
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GnomAD4 genome ? AF: 0.0000132 AC: 2AN: 151986Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74218
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neurodevelopmental disorder with seizures, microcephaly, and brain abnormalities Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Aug 31, 2022 | - - |
Seizure;C0036857:Intellectual disability, severe;C0270685:Cerebral calcification;C4551563:Microcephaly Pathogenic:1
Pathogenic, criteria provided, single submitter | research | Institute of Human Genetics, University of Leipzig Medical Center | Apr 14, 2022 | The variant was identified as homozygous. Criteria applied: PVS1, PM2_Supporting, PM3_Supporting - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
MutationTaster
Benign
A;A;A;D;D
Vest4
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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